Tetrahydropyrimidone inhibitors of fatty acid binding protein and method

ABSTRACT

aP2 inhibiting compounds are provided having the formula  
                 
 
     wherein A, B, X, and Y are as described herein.  
     A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing such aP2 inhibitor or a combination of such aP2 inhibitor and another antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.

[0001] This application claims priority to U.S. Provisional applicationSer. No. 60/178,598 filed Jan. 28, 2000 the entirety of which isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to tetrahydropyrimidones which areinhibitors of fatty acid binding protein (aP2) and to a method fortreating diabetes, especially Type II diabetes, as well ashyperglycemia, hyperinsulinemia, obesity, Syndrome X, diabeticcomplications, atherosclerosis and related diseases, and other chronicinflammatory and autoimmune/inflammatory diseases, employing suchtetrahydropyrimidones alone alone or in combination with one or moretypes of therapuetic agents. In addition, the compounds of the presentinvention act as inhibitors of aldose reductase and thus are useful inthe treatment of diabetic complications such as diabetic retinopathy,diabetic neuropathy and diabetic nephropathy.

BACKGROUND OF THE INVENTION

[0003] Fatty acid binding proteins (FABPs) are small cytoplasmicproteins that bind to fatty acids such as oleic acids which areimportant metabolic fuels and cellular regulators. Dysregulation offatty acid metabolism in adipose tissue is a prominent feature ofinsulin resistance and the transition from obesity to non-insulindependent diabetes mellitus (NIDDM or Type II diabetes).

[0004] aP2 (adipocyte fatty binding protein), an abundant 14.6 KDacytosolic protein in adipocytes, and one of a family of homologousintracellular fatty acid binding proteins (FABPs), is involved in theregulation of fatty acid trafficking in adipocytes and mediates fattyacid fluxes in adipose tissue. G. S. Hotamisligil et al, “Uncoupling ofObesity from Insulin Resistance Through a Targeted Mutation in aP2, theAdipocyte Fatty Acid Binding Protein”, Science, Vol. 274, Nov. 22, 1996,pp. 1377-1379, report that aP2-deficient mice placed on a high fat dietfor several weeks developed dietary obesity, but, unlike control-mice ona similar diet, did not develop insulin resistance or diabetes.Hotamisligil et al conclude “aP2 is central to the pathway that linksobesity to insulin resistance” (Abstract, page 1377).

[0005] DIALOG ALERT DBDR928 dated Jan. 2, 1997, Pharmaprojects No. 5149(Knight-Ridder Information) discloses that a major drug company “isusing virtual screening techniques to identify potential newantidiabetic compounds.” It is reported that “the company is screeningusing aP2, a protein related to adipocyte fatty acid binding protein.”

[0006] U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999(attorney file LA24A) and U.S. application Ser. No. 09/519,079 filedMar. 6, 2000 (attorney file LA27) disclose methods for treating diabetesemploying an aP2 inhibitor.

DESCRIPTION OF THE INVENTION

[0007] In accordance with the present invention, tetrahydropyrimidonecompounds are provided which have the structure of formula I

[0008] including pharmaceutically acceptable salts thereof, prodrugesters thereof, and all stereoisomers thereof, wherein

[0009] A and B are the same or different and are independently

[0010] —J,

[0011] —(CR³R⁴)_(n)—J,

[0012] —R⁵(CR³R⁴)_(p)—J,

[0013] —(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—J,

[0014] —(CR³R⁴)_(n)(CR⁶R⁷)_(p)—J,

[0015] —S(O)J where J is other than hydrogen, —S(O₂)J where J is otherthan hydrogen, and

[0016] —NH(CR³R⁴)_(n)—J;

[0017] J is independently R¹ or R²;

[0018] R¹ and R² are independently hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl andsubstituted cycloheteroalkyl;

[0019] R³ and R⁴ are the same or different and are independently H,alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxycarbonyl,alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl,arylcarbonyl, aryl and heteroaryl, halo, hydroxy, alkoxy and aryloxy;

[0020] or R³ and R⁴ together with the atom to which they are bonded mayform a 3 to 9-membered saturated or unsaturated ring.

[0021] R⁵ is a bond, O, NR⁸, S, SO, SO₂, CO or CONH;

[0022] R⁶ and R⁷ are the same or different and are independently H,alkyl, cycloalkyl, aryl, hydroxy, amino, halo, alkoxy, aryloxy,alkylthio, arylthio, alkylamino, dialkylamino, arylamino, diarylamino,alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino;

[0023] R⁸ is H, aryl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkyl oralkylcarbonyl;

[0024] R⁹ is H, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a prodrugester thereof;

[0025] R¹⁰ is H, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a prodrugester thereof;

[0026] R¹¹ is hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl,substituted heteroaralkyl, cycloheteroalkyl and substitutedcycloheteroalkyl;

[0027] R¹² and R¹³ are the same or different and are independently H,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl,aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl or a pro drug esterthereof;

[0028] or R¹² and R¹³ together with the nitrogen atom to which they arebonded together form an optionally substituted cycloheteroalkyl ring;

[0029] X is selected from —Z, —(CR³R⁴)_(n)—Z, —O—(CR³R⁴)_(p)—Z,—S—(CR³R⁴)_(p)—Z, —NHC(═O)Z, —CH═CHZ, -(cycloalkylene)-Z, or—N(R⁸)(CR³R⁴)_(n)—Z;

[0030] Y is H, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio,arylthio, hydroxy, —(CR³R⁴)_(n)—CO₂R⁹, —(CR³R⁴)_(n)—CONR¹²R¹³, —NR³R⁴,aralkoxy, or heteroarylalkyl, provided that Y is other than hydroxy orNH₂ when X is —O(CR³R⁴)_(p)—Z, —S(CR³R⁴)_(p)—Z, —NHC(═O)Z, or—N(R⁸)(CR³R⁴)_(n)—Z;

[0031] or X and Y, taken together with the atom to which they arejoined, provide a group of the formula

[0032] Z is CO₂R⁹, SO₃H, PO₃R⁹R¹⁰, CONHOH, CONR¹²R¹³, (CR³R⁴)_(m)OH, ortetrazole of the formula

[0033] or its tautomer;

[0034] n is an integer selected from 0 to 5;

[0035] m is an integer selected from 1 to 5; and

[0036] p is an integer selected from 0 to 4.

[0037] In addition, the present invention provides for novelintermediates useful in the synthesis of compounds of formula I. Suchintermediates have the structure of formula II

[0038] where A and B are as defined above,

[0039] X* is W, —(CR³R⁴)_(n)—W, —O(CR³R⁴)_(n)—W, —S(CR³R⁴)_(n)—W,—NHC(═O)W, —CH═CHW, -(cycloalkylene)-W, or —N(R⁸)(CR³R⁴)_(n)—W;

[0040] Y is H, alkyl, alkenyl, aryl, aralkyl, heteroarylalkyl, alkoxy,aryloxy, aralkoxy, alkylthio, arylthio, hydroxy, or NR³R⁴ provided thatY is other than hydroxy or NH₂ when X is —O(CR³R⁴)_(p)—W,—S(CR³R⁴)_(p)—W, —NHC(═O)W, or —N(R⁸)(CR³R⁴)_(n)—W;

[0041] W is cyano, halogen, hydroxy, alkenyl, C(O)Cl, or C(O)H.

[0042] or X* and Y, taken together with the atom to which they arejoined, provide a group of the formula

[0043] In addition, in accordance with the present invention, a methodis provided for treating diabetes, especially Type II diabetes, andrelated diseases such as insulin resistance, hyperglycemia,hyperinsulinemia, elevated blood levels of fatty acids or glycerol,obesity, hypertriglyceridemia, atherosclerosis, inflammation, diabeticretinopathy, diabetic neuropathy and diabetic nephropathy wherein atherapeutically effective amount of a compound of structure I isadministered to a human patient in need of treatment.

[0044] In addition, in accordance with the present invention, a methodis provided for treating diabetes and related diseases as defined aboveand hereinafter, wherein a therapeutically effective amount of acombination of a compound of structure I and another type antidiabeticagent is administered to a human patient in need of treatment.

[0045] In the above method of the invention, the compound of structure Iwill be employed in a weight ratio to another antidiabetic agent(depending upon its mode of operation) within the range from about0.01:1 to about 100:1, preferably from about 0.5:1 to about 10:1.

[0046] Examples of X moieties include (but are not limited to)

[0047] Preferred compounds of formula I include compounds where

[0048] A is (CR³R⁴)_(n)—R¹ where n is 0 to 5, and R³ and R⁴ are the sameor different and are selected from hydrogen, alkyl and substitutedalkyl;

[0049] R¹ is substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkyl or cycloalkyl;

[0050] B is R² or (CR³R⁴)_(n)—R² where n is 1 and R³ and R⁴ are the sameor different and are selected from hydrogen, alkyl and substitutedalkyl;

[0051] R² is aryl, substituted aryl, cycloalkylalkyl, heteroaryl orsubstituted heteroaryl;

[0052] Y is hydrogen, OH, —(CR³R⁴)_(n)—CONR¹²R¹³, or —(CR³R⁴)_(n)—CO₂R⁹;

[0053] X is (CR³R⁴)_(n)—Z where n is 0 or 1 and R³ and R⁴ are the sameor different and are selected from hydrogen, hydroxy, alkyl andsubstituted alkyl;

[0054] or X and Y, taken together with the atom to which they arejoined, provide a group of the formula

[0055] and

[0056] Z is CO₂R⁹, CONR¹²R¹³, PO₃H₂, CONHOH, or tetrazole.

[0057] More preferred compounds of formula I include compounds where Ais R¹;

[0058] R¹ is aryl (especially where aryl is phenyl), substituted aryl(especially where substituted with one or more halogen, alkoxy oraryloxy) or substituted alkyl (especially where substituted with one ormore alkoxy or aryloxy);

[0059] B is (CR³R⁴)_(n)—R² where n is 1 and R³ and R⁴ are hydrogen

[0060] R² is aryl (especially where aryl is phenyl or napthyl), orsubstituted aryl (especially substituted with one or more halogen,alkyl, substituted alkyl alkoxy; arylalkoxy, or cyano);

[0061] Y is hydrogen, OH, —(CR³R⁴)_(n)—CONR¹²R¹³, or —(CR³R⁴)_(n)—CO₂R⁹(especially where n is 1 and R³, R⁴ and R⁹ are each hydrogen);

[0062] X is —(CR³R⁴)_(n)—Z where n is 0 or 1 and R³ and R⁴ are hydrogen;and

[0063] Z is CO₂H, CONR¹²R¹³, or tetrazole.

[0064] Most preferred compounds of formula I include compounds where Ais R¹;

[0065] R¹ is substituted alkyl (especially where substituted with one ormore aryloxy), substituted aryl (especially where aryl is phenyl and thesubstituents are selected from halogens);

[0066] B is (CR³R⁴)_(n)—R² where n is 1 and R³ and R⁴ are hydrogen

[0067] R² is aryl (especially where aryl is phenyl or napthyl), orsubstituted aryl (especially where the substituents are selected fromhalogen, and alkoxy);

[0068] Y is hydrogen, —(CR³R⁴)_(n)—CONR¹²R¹³, or —(CR³R⁴)_(n)—CO₂R⁹where n is 1 and R³, R⁴ and R⁹ are each hydrogen;

[0069] X is —(CR³R⁴)_(n)—Z where n is 1 and R³ and R⁴ are hydrogen; and

[0070] Z is CO₂H or CONR¹²R¹³ (especially where R¹² and R¹³ areindependently hydrogen, optionally substituted aryl or optionallysubstituted cycloheteroalkyl).

DETAILED DESCRIPTION OF THE INVENTION

[0071] Compounds of the invention of general structure I may besynthesized as illustrated in the schemes set forth below.

[0072] Amine 2 is converted to carbamate 3 followed by alkylation with3-bromomethacrylate to provide 4. Congugate addition of 4 with thedesired amine provides 5. Removal of the Boc protecting group from 5,with 4N HCl/dioxane, provides 6. Cyclization of 6, with phosgene andtriethylamine, provides cyclic urea 7. Reduction of 7 with lithiumborohydride provides alcohol 8 which is transformed into iodide 9 andthen nitrile 10. Hydrolysis of 10 provides compound I_(a).

[0073] Alternatively, alchohol 8 can be synthesized from isocyanate 11by treatment with an appropriate amine to form urea 12, which uponreaction with 2-chloromethyl-1-chloro-2-propene and two equivalents ofsodium hydride provides cyclic urea intermediate 13. Hydroboration of 13provides alchohol 8.

[0074] Alternatively I_(a) can be formed from isocyanate 11 by treatmentwith para-anisole to provide urea 14. Phase-transfer catalyzedalkylation of 14 with the known bis-mesylate 37 (see scheme 4) providescyclic urea 15. Cleavage of 15 and subsequent oxidation/methanolysisprovides ester 16. Removal of the methoxyphenyl protecting group byknown methods (e.g., ceric ammonium nitrate) provides 17. Reaction of 17with an appropriate bromide provides 18 which upon saponificationprovides I_(a).

[0075] Additional compounds within formula I can be generated fromcompounds disclosed in schemes 1 through 3 through conversion of thesubstituent groups to other functionality by the usual methods ofchemical synthesis, as illustrated in the following schemes 5 through16, and the following examples. In generating such additional compoundsone skilled in the art will recognize that it may be necessary toprotect reactive functionalilty such as hydroxy, amino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in reactions. The introduction and removal ofprotecting groups are well known to those skilled in the art (forexample see Green, T. W., “Protective Groups in Organic Synthesis”, JohnWiley and Sons 1991).

[0076] Unless otherwise indicated, the term “lower alkyl”, “alkyl” or“alk” as employed herein alone or as part of another group includes bothstraight and branched chain hydrocarbons, containing 1 to 20 carbons,preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in thenormal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like as well as such groupsincluding 1 to 4 substituents such as halo, for example F, Br, Cl or Ior CF₃, alkoxy, (alkoxy)alkoxy, alkoxyalkyl, (hydroxy)alkoxyalkyl,(alkoxy)alkoxyalkyl, aryl, aryloxy, (aryl)aryl or diaryl,(aryl)alkoxyaryl, diaryl, arylalkyl, (aryl)alkoxy, (aryl)alkoxyalkyl,(aryloxy)aralkyl, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, substituted amino, alkylamino, hydroxy,hydroxyalkyl, hydroxycarbonyl, alkylcarbonyl, alkoxycarbonyl,arylcarbonyl, acyl, cycloheteroalkyl, (cycloheteroalkyl)alkyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, aryloxyaryl, (amino)carbonyl, (substituted amino)carbonyl,alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,trihaloalkyl and/or alkylthio (where the alkyl radical is optionallysubstituted), arylthio (where the aryl radical is optionallysubstituted), sulfonylaryl and/or any of the R¹ groups. Where particularsubstituted alkyl groups are identified herein they are named by addingthe term “alkyl” at the end of the name of the substituent radical(e.g., aralkyl, heteroaralkyl etc.).

[0077] Unless otherwise indicated, the term “cycloalkyl” as employedherein alone or as part of another group includes saturated or partiallyunsaturated (containing 1 or more double bonds) cyclic hydrocarbongroups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyland tricyclicalkyl, containing a total of 3 to 20 carbons forming therings, preferably 3 to 10 carbons, forming the ring and which may befused to 1 or 2 aromatic rings as described for aryl, or joined by spirounion to other cycloalkyl rings or heterocycloalkyl rings. Cycloalkylrings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,

[0078] any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio and/orany of the R¹ groups.

[0079] The term “cycloalkenyl” as employed herein alone or as part ofanother group refers to cyclic hydrocarbons containing 3 to 12 carbons,preferably 5 to 10 carbons and 1 or more double bonds. Exemplarycycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may beoptionally substituted as defined for cycloalkyl.

[0080] The term “cycloalkylene” as employed herein refers to a“cycloalkyl” group which includes free bonds and thus is a linking groupsuch as

[0081] and the like, and may optionally be substituted as defined abovefor “cycloalkyl”.

[0082] The term “alkanoyl” as used herein alone or as part of anothergroup refers to alkyl linked to a carbonyl group.

[0083] Unless otherwise indicated, the term “lower alkenyl” or “alkenyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons, and more preferably 1 to 8 carbons in the normal chain, whichinclude one to six double bonds in the normal chain, such as vinyl,2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl,3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl,4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and thelike, and which may be optionally substituted with 1 to 4 substituents,namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl,arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl,alkanoylamino, alkylamido, arylcarbonyl-amino, nitro, cyano, thiol,alkylthio and/or any of the alkyl substituent groups.

[0084] Unless otherwise indicated, the term “lower alkynyl” or “alkynyl”as used herein by itself or as part of another group refers to straightor branched chain radicals of 2 to 20 carbons, preferably 2 to 12carbons and more preferably 2 to 8 carbons in the normal chain, whichinclude one triple bond in the normal chain, such as 2-propynyl,3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl,2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido,arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, and/or any ofthe alkyl substituents.

[0085] The terms “arylalkenyl” and “arylalkynyl” as used alone or aspart of another group refer to alkenyl and alkynyl groups as describedabove having an aryl substituent.

[0086] Where alkyl groups as defined above have single bonds forattaclunent to other groups at two different carbon atoms, they aretermed “alkylene” groups and may optionally be substituted as definedabove for “alkyl”.

[0087] Where alkenyl groups as defined above and alkynyl groups asdefined above, respectively, have single bonds for attachment at twodifferent carbon atoms, they are termed “alkenylene groups” and“alkynylene groups”, respectively, and may optionally be substituted asdefined above for “alkenyl” and “alkynyl”.

[0088] Suitable alkylene, alkenylene or alkynylene groups (CH₂)_(x) or(CH₂)_(y) (where, y is 1 to 8, preferably 1 to 5, and x is 1 to 5,preferably 1 to 3, which includes alkylene, alkenylene or alkynylenegroups) as defined herein, may optionally include 1, 2, or 3substituents which include alkyl, alkenyl, halogen, cyano, hydroxy,alkoxy, amino, thioalkyl, keto, C₃-C₆ cycloalkyl, alkylcarbonylamino oralkylcarbonyloxy.

[0089] Examples of (CH₂)_(x) or (CH₂)_(y), alkylene, alkenylene andalkynylene include

[0090] The term “halogen” or “halo” as used herein alone or as part ofanother group refers to chlorine, bromine, fluorine, and iodine as wellas CF₃, with chlorine, bromine or fluorine being preferred.

[0091] The term “metal ion” refers to alkali metal ions such as sodium,potassium or lithium and alkaline earth metal ions such as magnesium andcalcium, as well as zinc and aluminum.

[0092] Unless otherwise indicated, the terms “aryl” or “ar” as employedherein alone or as part of another group refers to monocyclic andbicyclic aromatic groups containing 6 to 10 carbons in the ring portion(such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and mayoptionally include one to three additional rings fused to a carbocyclicring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl orcycloheteroalkyl rings for example

[0093] and may be optionally substituted through available carbon atomswith 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl,substituted alkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloheteroalkyl, cycloheteroalkylalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, (aryl)alkyl, aryloxy,(aryloxy)alkyl, (aryl)alkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino, thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, aminocarbonyl, (substituted amino)carbonyl,(alkyl)aminocarbonyl, (substituted alkyl)aminocarbonyl,(aryl)aminocarbonyl, (substituted aryl)aminocarbonyl, alkoxycarbonyl,(amino)alkoxycarbonyl, (substituted amino)alkoxycarbonyl,alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonylaminocarbonyl, sulfonylaryl, (alkyl)sulfonylaryl,sulfonylarylalkyl, (alkyl)sulfonylaralalkyl, and/or any of the R¹groups.

[0094] Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”,“aryloxy” or “aralkoxy” as employed herein alone or as part of anothergroup includes any of the above alkyl, aralkyl or aryl groups linked toan oxygen atom.

[0095] Unless otherwise indicated, the term “substituted amino” asemployed herein alone or as part of another group refers to aminosubstituted with one or two substituents, which may be the same ordifferent, such as alkyl (optionally substituted), aryl (optionallysubstituted), arylalkyl (optionally substituted), arylalkyl (optionallysubstituted), heteroaryl (optionally substituted), heteroarylalkyl(optionally substituted), cycloheteroalkyl (optionally substituted),(cycloheteroalkyl)alkyl (optionally substituted), cycloalkyl (optionallysubstituted), cycloalkylalkyl (optionally substituted), haloalkyl(optionally substituted), hydroxyalkyl (optionally substituted),alkoxyalkyl (optionally substituted) or thioalkyl (optionallysubstituted). In addition, the amino substituents may be taken togetherwith the nitrogen atom to which they are attached to form1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl,

[0096] or 1-azepinyl, optionally substituted with alkyl, substitutedalkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl orsubstituted aryl.

[0097] Unless otherwise indicated, the term “lower alkylthio”,alkylthio”, “arylthio” or “aralkylthio” as employed herein alone or aspart of another group includes any of the above alkyl, aralkyl or arylgroups linked to a sulfur atom.

[0098] Unless otherwise indicated, the term “lower alkylamino”,“alkylamino”, “arylamino”, or “arylalkylamino” as employed herein aloneor as part of another group includes any of the above alkyl, aryl orarylalkyl groups linked to a nitrogen atom.

[0099] Unless otherwise indicated, the term “acyl” as employed herein byitself or part of another group, as defined herein, refers to an organicradical linked to a carbonyl group (i.e., —

[0100] —R); examples of acyl groups include any of the R¹ groupsattached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl,heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like. Suchgroups may also be identified by adding the term “carbonyl” at the endof the name of the organic radical R bonded to the acyl group (e.g.,alkylaminocarbonyl, alkoxycarbonyl, etc).

[0101] Unless otherwise indicated, the term “cycloheteroalkyl” as usedherein alone or as part of another group refers to a 5-, 6- or7-membered saturated or partially unsaturated ring which includes 1 ormore hetero atoms such as nitrogen, oxygen and/or sulfur, linked througha carbon atom or a heteroatom, where possible, optionally via the linker(CH₂)_(x), such as

[0102] and the like. The above groups may include 1 to 4 substituentssuch as alkyl, substituted alkyl, halo, oxo, aryl, substituted aryl,aralkyl, substituted aralkyl and/or any of the R¹ groups. In addition,any of the cycloheteroalkyl rings can be fused to a cycloalkyl, aryl,heteroaryl or cycloheteroalkyl ring. In addition, any of thecycloheteroalkyl rings can be joined by spiro union to cycloalkyl ringsor other heterocycloalkyl rings.

[0103] Unless otherwise indicated, the term “heteroaryl” as used hereinalone or as part of another group refers to monocyclic and bicyclicaromatic rings containing from 5 to 10 atoms, which includes 1, 2, 3 or4 hetero atoms such as nitrogen, oxygen or sulfur, and such rings fusedto an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g.benzothiophenyl, indolyl), where the nitrogen and sulfur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally bequaternized. The heteroaryl group may optionally include 1 to 4substituents such as halo, haloalkyl, alkyl, substituted alkyl, alkoxy,haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl,cycloalkyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino orarylsulfonylaminocarbonyl, sulfonylaryl, sulfonylarylalkyl, and/or anyof the R¹ groups. Examples of heteroaryl groups include the following:

[0104] and the like.

[0105] The term “cycloheteroalkylalkyl” as used herein alone or as partof another group refers to cycloheteroalkyl groups as defined abovelinked through a C atom or heteroatom to a (CH₂)_(x) chain.

[0106] The term “heteroarylalkyl” or “heteroarylalkenyl” as used hereinalone or as part of another group refers to a heteroaryl group asdefined above linked through a C atom or heteroatom to a —(CH₂)_(x)—chain, alkylene or alkenylene as defined above.

[0107] The term “polyhaloalkyl” as used herein refers to an “alkyl”group as defined above which includes from 2 to 9, preferably from 2 to5, halo substituents, such as F or Cl, preferably F, such as CF₃CH₂, CF₃or CF₃CF₂CH₂.

[0108] The term “polyhaloalkyloxy” as used herein refers to an “alkoxy”or “alkyloxy” group as defined above which includes from 2 to 9,preferably from 2 to 5, halo substituents, such as F or Cl, preferablyF, such as CF₃CH₂O, CF₃O or CF₃CF₂CH₂O.

[0109] The term “prodrug esters” as employed herein includes prodrugesters which are known in the art for carboxylic acids such as similarcarboxylic acid esters such as methyl, ethyl benzyl and the like. Otherexamples include the following groups: (1-alkanoyloxy)alkyl such as,

[0110] wherein R^(a), R^(b) and R^(c) are H, alkyl, aryl or aryl-alkyl;however R^(a)O cannot be HO, and where Z¹ is

[0111] Examples of such prodrug esters include

[0112] Other examples of suitable prodrug esters include

[0113] wherein R^(a) can be H, alkyl (such as methyl or t-butyl),arylalkyl (such as benzyl) or aryl (such as phenyl); R^(d) is H, alkyl,halogen or alkoxy, R^(e) is alkyl, aryl, arylalkyl or alkoxyl, and n₁ is0, 1 or 2.

[0114] The compounds of formula I form salts which are also within thescope of this invention. Reference to a compound of the formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains a both a basic moietyand an acidic moiety, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful, e.g., in isolation orpurification steps which may be employed during preparation. Salts ofthe compounds of the formula I may be formed, for example, by reacting acompound I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

[0115] The compounds of formula I which contain a basic moiety may formsalts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

[0116] The compounds of formula I which contain an acidic moiety mayform salts with a variety of organic and inorganic bases. Exemplarybasic salts include ammonium salts, alkali metal salts such as sodium,lithium, and potassium salts, alkaline earth metal salts such as calciumand magnesium salts, salts with organic bases (for example, organicamines) such as benzathines, dicyclohexylamines, hydrabamines (formedwith N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

[0117] Basic nitrogen-containing groups may be quatemized with agentssuch as lower alkyl halides (e.g. methyl, ethyl, propyl, and butylchlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl,diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkylhalides (e.g. benzyl and phenethyl bromides), and others.

[0118] Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I are preferably hydrates.

[0119] To the extent that compounds of the formula I, and salts thereof,may exist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

[0120] All stereoisomers of the present compounds, such as those whichmay exist due to asymmetric carbons on the various substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons) and diastereomeric forms, are contemplated withinthe scope of this invention. Individual stereoisomers of the compoundsof the invention may, for example, be substantially free of otherisomers, or may be admixed, for example, as racemates or with all other,or other selected, stereoisomers. The chiral centers of the presentinvention can have the S or R configuration as defined by the IUPAC 1974Recommendations. When diastereomeric or enantiomeric products areprepared, they can be separated by conventional methods for example,chromatographic or fractional crystallization.

[0121] Where desired, the compounds of structure I may be used incombination with one or more other types of therapeutic agents which maybe administered orally in the same dosage form, in a separate oraldosage form or by injection.

[0122] The other type of therapeutic agent which may be optionallyemployed in combination with the aP2 inhibitor of formula I may be 1, 2,3 or more antidiabetic agents or antihyperglycemic agents includinginsulin secretagogues or insulin sensitizers, or other antidiabeticagents preferably having a mechanism of action different from aP2inhibition and may include biguanides, sulfonyl ureas, glucosidaseinhibitors, glycogen phosphorylase inhibitors, PPAR γ agonists, such asthiazolidinediones, SGLT2 inhibitors, PPAR α/γ dual agonists, dipeptidylpeptidase IV (DP4) inhibitors, and/or meglitinides, as well as insulin,and/or glucagon-like peptide-1 (GLP-1).

[0123] It is believed that the use of the compounds of structure I incombination with another antidiabetic agent produces antihyperglycemicresults greater than that possible from each of these medicaments aloneand greater than the combined additive anti-hyperglycemic effectsproduced by these medicaments.

[0124] The other antidiabetic agent may be an oral antihyperglycemicagent preferably a biguanide such as metformin or phenformin or saltsthereof, preferably metformin HCl.

[0125] Where the other antidiabetic agent is a biguanide, the compoundsof structure I will be employed in a weight ratio to biguanide withinthe range from about 0.01:1 to about 100:1, preferably from about 0.1:1to about 5:1.

[0126] The other antidiabetic agent may also preferably be a sulfonylurea such as glyburide (also known as glibenclamide), glimepiride(disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide orchlorpropamide, other known sulfonylureas or other antihyperglycemicagents which act on the ATP-dependent channel of the β-cells, withglyburide and glipizide being preferred, which may be administered inthe same or in separate oral dosage forms.

[0127] The compounds of structure I will be employed in a weight ratioto the sulfonyl urea in the range from about 0.01:1 to about 100:1,preferably from about 0.2:1 to about 10:1.

[0128] The oral antidiabetic agent may also be a glucosidase inhibitorsuch as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol(disclosed in U.S. Pat. No. 4,639,436), which may be administered in thesame or in a separate oral dosage forms.

[0129] The compounds of structure I will be employed in a weight ratioto the glucosidase inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.5:1 to about 50:1.

[0130] The compounds of structure I may be employed in combination witha PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent orother insulin sensitizers (which has an insulin sensitivity effect inNIDDM patients) such as troglitazone (Wamer-Lambert's Rezulin®,disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB), pioglitazone(Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016),Glaxo-Welcome's GL-262570, englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT-501(JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone andpioglitazone.

[0131] The compounds of structure I will be employed in a weight ratioto the thiazolidinedione in an amount within the range from about 0.01:1to about 100:1, preferably from about 0.1:1 to about 10:1.

[0132] The sulfonyl urea and insulin sensitizer in amounts of less thanabout 150 mg oral antidiabetic agent may be incorporated in a singletablet with the compounds of structure I.

[0133] The compounds of structure I may also be employed in combinationwith a antihyperglycemic agent such as insulin or with glucagon-likepeptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide,GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, thedisclosure of which is incorporated herein by reference), as well asAC2993 (Amylen) and LY-315902 (Lilly), which may be administered viainjection, intranasal, or by transdermal or buccal devices.

[0134] Where present, metformin, the sulfonyl ureas, such as glyburide,glimepiride, glipyride, glipizide, chlorpropamide and gliclazide and theglucosidase inhibitors acarbose or miglitol or insulin (injectable,pulmonary, buccal, or oral) may be employed in formulations as describedabove and in amounts and dosing as indicated in the Physician's DeskReference (PDR).

[0135] Where present, metformin or salt thereof may be employed inamounts within the range from about 500 to about 2000 mg per day whichmay be administered in single or divided doses one to four times daily.

[0136] Where present, the thiazolidinedione anti-diabetic agent may beemployed in amounts within the range from about 0.01 to about 2000mg/day which may be administered in single or divided doses one to fourtimes per day.

[0137] Where present insulin may be employed in formulations, amountsand dosing as indicated by the Physician's Desk Reference.

[0138] Where present GLP-1 peptides may be administered in oral buccalformulations, by nasal administration or parenterally as described inU.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which areincorporated herein by reference.

[0139] The other antidiabetic agent may also be a PPAR α/γ dual agonistsuch as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297(Kyorin Merck) as well as those disclosed by Murakami et al, “A NovelInsulin Sensitizer Acts As a Coligand for PeroxisomeProliferation—Activated Receptor Alpha (PPAR alpha) and PPAR gamma.Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver ofZucker Fatty Rats”, Diabetes 47, 1841-1847 (1998), and in U.S.provisional application No. 60/155,400, filed Sep. 22, 1999, (attorneyfile LA29) the disclosure of which is incorporated herein by reference,employing dosages as set out therein, which compounds designated aspreferred are preferred for use herein.

[0140] The other antidiabetic agent may be an SGLT2 inhibitor such asdisclosed in U.S. provisional application No. 60/158,773, filed Oct. 12,1999 (attorney file LA49), employing dosages as set out herein.Preferred are the compounds designated as preferred in the aboveapplication.

[0141] The other antidiabetic agent may be a DP4 inhibitor such asdisclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) (preferred) as disclosed by Hughes et al, Biochemistry,38(36), 11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540,2-cyanopyrrolidides and 4-cyanopyrrolidides as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996) employing dosages as set out in the above references.

[0142] The meglitinide which may optionally be employed in combinationwith the compound of formula I of the invention may be repaglinide,nateglinide (Novartis) or KAD1229 (PF/Kissei), with repaglinide beingpreferred.

[0143] The aP2 inhibitor of formula I will be employed in a weight ratioto the meglitinide, PPAR γ agonist, PPAR α/γ dual agonist, SGLT2inhibitor or DP4 inhibitor within the range from about 0.01:1 to about100:1, preferably from about 0.2:1 to about 10:1.

[0144] The compounds of structure I may also be employed in combinationwith one or more hypolipidemic agent, lipid-lowering agent or otherlipid agent. The hypolipidemic agent, lipid-lowering agent or otherlipid agent which may be optionally employed in combination with thecompounds of formula I of the invention may include 1, 2, 3 or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, nicotinic acid and derivatives thereof, and/orcholesterol ester transfer protein inhibitors such as CP-529414(Pfizer).

[0145] MTP inhibitors employed herein include MTP inhibitors disclosedin U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat. No.5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S. Pat.No. 5,885,983 and U.S. application Ser. No. 09/175,180 filed Oct. 20,1998, now U.S. Pat. No. 5,962,440. Preferred are each of the preferredMTP inhibitors disclosed in each of the above patents and applications.

[0146] All of the above U.S. Patents and applications are incorporatedherein by reference.

[0147] Most preferred MTP inhibitors to be employed in accordance withthe present invention include preferred MTP inhibitors as set out inU.S. Pat. Nos. 5,739,135 and 5,712,279, and U.S. Pat. No. 5,760,246.

[0148] The most preferred MTP inhibitor is9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide

[0149] The hypolipidemic agent may be an HMG CoA reductase inhibitorwhich includes, but is not limited to, mevastatin and related compoundsas disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) andrelated compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatinand related compounds such as disclosed in U.S. Pat. No. 4,346,227,simvastatin and related compounds as disclosed in U.S. Pat. Nos.4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may beemployed herein include, but are not limited to, fluvastatin, disclosedin U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos.5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos.4,681,893, 5,273,995, 5,385,929 and 5,686,104, atavastatin(Nissan/Sankyo's nisvastatin (NK-104)) disclosed in U.S. Pat. No.5,011,930, Shionogi-Astra/Zeneca rosuvastatin (ZD-4522) disclosed inU.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S.Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives as disclosed in PCT application WO 86/03488,6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin) as disclosed inEuropean Patent Application No.0,142,146 A2, and quinoline and pyridinederivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322.

[0150] In addition, phosphinic acid compounds useful in inhibiting HMGCoA reductase suitable for use herein are disclosed in GB 2205837.

[0151] The squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem.,1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996).

[0152] In addition, other squalene synthetase inhibitors suitable foruse herein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293,phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation,June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp16, 17, 40-43, 48-51, Summary.

[0153] Other hypolipidemic agents suitable for use herein include, butare not limited to, fibric acid derivatives, such as fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and thelike, probucol, and related compounds as disclosed in U.S. Pat. No.3,674,836, probucol and gemfibrozil being preferred, bile acidsequestrants such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

[0154] The other hypolipidemic agent may be an ACAT inhibitor such asdisclosed in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); “TheACAT inhibitor, C1-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis(Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile ofFCE 27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. DrugRev. (1998), 16(1), 16-30; “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al,Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. 6. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of aseries of substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureaswith enhanced hypocholesterolemic activity”, Stout et al, Chemtracts:Org. Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co.Ltd).

[0155] The hypolipidemic agent may be an upregulator of LD2 receptoractivity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427(Eli Lilly).

[0156] The hypolipidemic agent may be a cholesterol absorption inhibitorpreferably Schering-Plough's SCH48461 as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

[0157] The hypolipidemic agent may be an ileal Na⁺/bile acidcotransporter inhibitor such as disclosed in Drugs of the Future, 24,425-430 (1999).

[0158] Preferred hypolipidemic agents are pravastatin, lovastatin,simvastatin, atorvastatin, fluvastatin, cerivastatin, atavastatin andZD-4522.

[0159] The above-mentioned U.S. patents are incorporated herein byreference. The amounts and dosages employed will be as indicated in thePhysician's Desk Reference and/or in the patents set out above.

[0160] The compounds of formula I of the invention will be employed in aweight ratio to the hypolipidemic agent (were present), within the rangefrom about 500:1 to about 1:500, preferably from about 100:1 to about1:100.

[0161] The dose administered must be carefully adjusted according toage, weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

[0162] The dosages and formulations for the hypolipidemic agent will beas disclosed in the various patents and applications discussed above.

[0163] The dosages and formulations for the other hypolipidemic agent tobe employed, where applicable, will be as set out in the latest editionof the Physicians' Desk Reference.

[0164] For oral administration, a satisfactory result may be obtainedemploying the MTP inhibitor in an amount within the range of from about0.01 mg/kg to about 500 mg and preferably from about 0.1 mg to about 100mg, one to four times daily.

[0165] A preferred oral dosage form, such as tablets or capsules, willcontain the MTP inhibitor in an amount of from about 1 to about 500 mg,preferably from about 2 to about 400 mg, and more preferably from about5 to about 250 mg, one to four times daily.

[0166] For oral administration, a satisfactory result may be obtainedemploying an HMG CoA reductase inhibitor, for example, pravastatin,lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin indosages employed as indicated in the Physician's Desk Reference, such asin an amount within the range of from about 1 to 2000 mg, and preferablyfrom about 4 to about 200 mg.

[0167] The squalene synthetase inhibitor may be employed in dosages inan amount within the range of from about 10 mg to about 2000 mg andpreferably from about 25 mg to about 200 mg.

[0168] A preferred oral dosage form, such as tablets or capsules, willcontain the HMG CoA reductase inhibitor in an amount from about 0.1 toabout 100 mg, preferably from about 5 to about 80 mg, and morepreferably from about 10 to about 40 mg.

[0169] A preferred oral dosage form, such as tablets or capsules willcontain the squalene synthetase inhibitor in an amount of from about 10to about 500 mg, preferably from about 25 to about 200 mg.

[0170] The other hypolipidemic agent may also be a lipoxygenaseinhibitor including a 15-lipoxygenase (15-LO) inhibitor such asbenzimidazole derivatives as disclosed in WO 97/12615, 15-LO inhibitorsas disclosed in WO 97/12613, isothiazolones as disclosed in WO 96/38144,and 15-LO inhibitors as disclosed by Sendobry et al “Attenuation ofdiet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties,Brit. J. Pharmacology (1997) 120, 1199-1206, and Cornicelli et al,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20.

[0171] The compounds of formula I and the hypolipidemic agent may beemployed together in the same oral dosage form or in separate oraldosage forms taken at the same time.

[0172] The compositions described above may be administered in thedosage forms as described above in single or divided doses of one tofour times daily. It may be advisable to start a patient on a low dosecombination and work up gradually to a high dose combination.

[0173] The other type of therapeutic agent which may be optionallyemployed with the aP2 inhibitor of formula I may be 1, 2, 3 or more ofan anti-obesity agent including a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug and/or an anorectic agent.

[0174] The beta 3 adrenergic agonist which may be optionally employed incombination with a compound of formula I may be AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983 and 5,488,064, with AJ9677, L750,355 and CP331648being preferred.

[0175] The lipase inhibitor which may be optionally employed incombination with a compound of formula I may be orlistat or ATL-962(Alizyme), with orlistat being preferred.

[0176] The serotonin (and dopoamine) reuptake inhibitor which may beoptionally employed in combination with a compound of formula I may besibutramine, topiramate (Johnson & Johnson) or axokine (Regeneron), withsibutramine and topiramate being preferred.

[0177] The thyroid receptor beta compound which may be optionallyemployed in combination with a compound of formula I may be a thyroidreceptor ligand as disclosed in WO97/21993 (U. Cal SF), WO99/00353(KaroBio) and GB98/284425 (KaroBio), with compounds of the KaroBioapplications being preferred.

[0178] The anorectic agent which may be optionally employed incombination with a compound of formula I may be dexamphetamine,phentermine, phenylpropanolamine or mazindol, with dexamphetamine beingpreferred.

[0179] The various anti-obesity agents described above may be employedin the same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

[0180] The other type of therapeutic agent which may be optionallyemployed with the aP2 inhibitor of formula I may be 1, 2, 3 or more ofan antihypertensive agent including an ACE inhibitor, a vasopeptidaseinhibitor, an angiotensin II antagonist, a calcium channel blocker, apotassium channel opener, an alpha-blocker, a beta blocker, a centrallyacting alpha agonist, and/or a diuretic.

[0181] The ACE inhibitor which may be optionally employed in combinationwith a compound of formula I may be lisinopril, enalapril, quinapril,benazepril, fosinopril, fentiapril, ramipril, captopril, enalaprilat,moexipril, tranolapril, perindopril, ceranopril, zofenopril or cetapril.

[0182] Preferred ACE inhibitors are captopril, as well as fosinopril,enalapril, lisinopril, quinapril, benazepril, fentiapril, ramipril, andmoexipril.

[0183] The vasopeptidase inhibitor (also known as NEP/ACE inhibitors)which may be optionally employed with the aP2 inhibitor of formula I maybe omapatrilat (most preferred) and[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (BMS 189,921 also preferred), as well as those disclosed in U.S.Pat. Nos. 5,362,727, 5,366,973, 5,225,401, 4,722,810, 5,223,516,4,749,688. U.S. Pat. No. 5,504,080, U.S. Pat. No. 5,552,397, U.S. Pat.No. 5,612,359, U.S. Pat. No. 5,525,723, European Patent Application0599,444, 0481,522, 0599,444, 0595,610, European Patent Application0534363.A2, 534,396 and 534,492, and European Patent Application0629627.A2.

[0184] Preferred are those NEP/ACE inhibitors which are designated aspreferred in the above patents/applications which U.S.patents/applications are incorporated herein by reference.

[0185] The angiotensin II receptor antagonist (also referred to hereinas angiotensin II antagonist or AII antagonist) which may be optionallyemployed in combination with a compound of formula I may be irbesartan,losartan, valsartan, candesartan, telmisartan, tasosartan and/oreprosartan, with irbesartan or losartan being preferred.

[0186] The calcium channel blocker (also referred to as a calciumantagonist) which may be optionally employed in combination with acompound of formula I may be amlodipine, diltiazem, nifedipine,verapamil, feldodipine, nisoldipine, isradipine and/or nicardipine, withamlodipine, diltiazem, verapamil and nifedipine being preferred.

[0187] The alpha-blocker which may be optionally employed in combinationwith a compound of formula I may be terazosin, doxazosin or prazosin,all of which are preferred.

[0188] The beta-blocker which may be optionally employed in combinationwith a compound of formula I may be nadolol, atenolol, propranolol,metoprolol, carvediol or sotalol, with atenolol and nadolol beingpreferred.

[0189] The potassium channel opener which may be optionally employed incombination with a compound of formula I may be minoxidil.

[0190] The centrally acting cc agonist antihypertensive agent which maybe optionally employed in combination with a compound of formula I maybe clonidine or guanfacine, with clonidine being preferred.

[0191] The diuretic which may be optionally employed in connection witha compound of formula I may be hydrochlorothiazide, torasemide,furosemide, spironolactone and/or indapamide, with hydrochlorothiazideand furosemide being preferred.

[0192] The antiplatelet agent (also known as platelet aggregationinhibitor) which may be optionally employed in combination with acompound of formula I may be aspirin, clopidogrel, ticlopidine,dipyridamole, abciximab, tirofiban, eptifibatide, anagrelide and/orifetroban, with aspirin and clopidogrel being preferred.

[0193] The anti-infective agent which may be optionally employed incombination with a compound of formula I may be an anti-infective thatis effective against chlamydial infections, such as azithromycin,gatifloxacin, ciprofloxacin, levofloxacin and trovafloxacin, withazithromycin and gatifloxacin being preferred.

[0194] The various antihypertensive agents and antiplatelet agents andanti-infective agents described above may be employed in the same dosageform with the compound of formula I or in different dosage forms, indosages and regimens as generally known in the art or in the PDR.

[0195] In carrying our the method of the invention, a pharmaceuticalcomposition will be employed containing the compounds of structure I,with or without another therapeutic agent, in association with apharmaceutical vehicle or diluent. The pharmaceutical composition can beformulated employing conventional solid or liquid vehicles or diluentsand pharmaceutical additives of a type appropriate to the mode ofdesired administration. The compounds can be administered to mammalianspecies including humans, monkeys, dogs, etc. by an oral route, forexample, in the form of tablets, capsules, granules or powders, or theycan be administered by a parenteral route in the form of injectablepreparations. The dose for adults is preferably between 20 and 2,000 mgper day, which can be administered in a single dose or in the form ofindividual doses from 1-4 times per day.

[0196] A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg) and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

[0197] A typical injectable preparation is produced by asepticallyplacing 250 mg of compounds of structure I into a vial, asepticallyfreeze-drying and sealing. For use, the contents of the vial are mixedwith 2 mL of physiological saline, to produce an injectable preparation.

[0198] aP2 inhibitor activity of the compounds of the invention may bedetermined by use of an in vitro assay system which measures thepotentiation of inhibition of aP2 by displacement of a fluorescentsubstrate from aP2 by the inhibitor. Inhibition constants (Ki values)for the aP2 inhibitors of the invention may be determined by the methoddescribed below:

[0199] Production of purified recombinant human aP2 protein. Recombinanthuman aP2 protein is produced by standard recombinant DNA technology. Inthe typical case, aP2 is produced by heterologous expression in E. colistrain BL21(D53) transformed with pETlla vector containing the fulllength human aP2 cDNA (Baxa, C. A., Sha, R. S., Buelt, M. K., Smith, A.J., Matarese, V., Chinander, L. L., Boundy, K. L., and Bernlohr, D. A.(1989). Human adipocyte lipid-binding protein: purification of theprotein and cloning of its complementary DNA. Biochemistry 28: 8683-8690and Xu, Z., Buelt, M. K., Banaszak, L. J., and Bemlohr, D. A. (1991).Expression, purification and crystallization of the adipocyte lipidbinding protein. J. Biol. Chem. 266:14367-14370). Purification of aP2from E. coli is conducted as described by Xu, yielding essentiallyhomogeneous aP2 protein with molecular weight ˜14600 daltons and free ofendogenous fatty acids. The purified aP2 is capable of binding up to onemole of free fatty acid per mole protein. The binding and structuralproperties of recombinant aP2 protein were previously shown to beidentical to aP2 protein isolated from adipose tissue.

[0200] In vitro assay of aP2 inhibitors. Inhibitors of aP2 are evaluatedin a homogeneous fluorescent-based competition assay using recombinantaP2 protein and 1,8-anilino-naphthalene-sulfonic acid (1,8-ANS) as assaysubstrate. This competition assay was adapted from generalizedprocedures described previously (Kane, C. D. and Bernlohr, D. A. (1996).A simple assay for intracellular lipid-binding proteins usingdisplacement of 1-anilino-8-sulfonic acid. (1996) Anal. Biochem.233:197-204 and Kurian E., Kirk, W. R. and Prendergast, F. G. (1996)Affinity of fatty acid for r-rat intestinal fatty acid binding protein.Biochemistry, 35, 3865-3874). The method relies on the increase influorescence quantum yield of 1,8-ANS upon binding to the fatty acidbinding site of aP2. The assay is run using appropriate concentrationsof inhibitor, 1,8-ANS, and aP2 protein, in order to calculate theinhibitor binding constant (Ki) for compounds being evaluated. The Kicalculation was based on the procedure previously described forcalculation of dissociation constants described by Kurian. Lower Kivalues indicate higher affinities of compounds binding to aP2.

[0201] In the assay as conducted for the inhibitors described herein, aseries of aliquots of aP2 (5 μM) in solution in 10 mM potassiumphosphate buffer (pH 7.0) are mixed with an equimolar concentration oftest compound, followed by the addition of a series of increasingconcentrations of 1,8-ANS (from 0 to 5 μM). The assay typically isconducted in 96-well plate format with reagents added using roboticinstrumentation (Packard Multiprobe 104). The fluorescence value foreach test is determined using a Cytofluor-4000 multi-well fluorescenceplate reader (Perceptive Biosystems) using excitation wavelength 360 nmand emission wavelength 460 nm, or using other suitablespectrofluorometer. In preparation for the assay, test compounds areinitially prepared at 10 mM in dimethylsulfoxide. All subsequentdilutions and assay additions are made in 10 mM potassium phosphatebuffer, pH 7.0.

[0202] X-ray crystallography of the inhibitor-aP2 complex can beperformed by one skilled in the art using contemporary biophysicalmethodologies and commercial instrumentation. Such crystallographic datacan be used to conclusively determine if a compound used in the presentinvention has embodied the structural requirement necessary forinhibition of aP2. An example of such an X-ray crystallographicdetermination is presented below:

[0203] Crystals of aP2 complexed with the inhibitors were typicallygrown by the hanging drop method. aP2, at 8.3 mg/ml, waspre-equilibrated with 1-5 mM of the inhibitor in 0.1M Tris-HCl pH 8.0,1% w/v DMSO for four hours. 2 μl drops containing equilibrated proteinand reservoir solution at a 1:1 ratio were suspended on plastic coverslips and equilibrated against a 1 ml reservoir containing 2.6-3.0Mammonium sulfate in 0.1M Tris-HCl pH 8.0. Crystals typically appeared in2-3 days and reached maximum size within 2 weeks. Data was typicallycollected on a single flash-frozen crystal (Oxford Cryosystems) using aRigaku rotating anode and an R-axis II image plate detector of a Brukermultiwire area detector. Diffraction from aP2 crystals was excellent.Diffraction was consistently observed to better than 2.0 Å resolutionoften to beyond 1.5 Å resolution. Data was processed either withDENZO/SCALEPACK (R-axis II data), or Xengen (Bruker data). XPLOR wasused for structure refinement and model building was done using themolecular modeling package CHAIN. After a single round of refinement,examination of the F_(o)-F_(c) map typically allowed facile building ofthe inhibitor into aP2 binding cavity. Iterative fitting and refinementwere continued until improvement was no longer seen in the electrondensity map or R-free.

[0204] The following Examples illustrate embodiments of the presentinvention, and are not intended to limit the scope of the claims.Abbreviations employed herein are defined below. Compounds of theExamples are identified by the example and step in which they areprepared (for example, “1A” denotes the title compounds of step A ofExample 1), or by the example only where the compound is the titlecompound of the example (for example “4” denotes the title comound ofExample 4).

[0205] 9-BBN=9-borabicyclo[3.3.1]nonane

[0206] Calc=calculated

[0207] DiBAl=diisobutylaluminum hydride

[0208] DMAP=Dimethylaminopyridine

[0209] DMF=dimethylformamide

[0210] DMSO=dimethylsulfoxide

[0211] Et=ethyl

[0212] Fnd=found

[0213] h=hours

[0214] LC/MS=liquid chromatography/mass spectrometry

[0215] LDA=lithium diisopropylamide

[0216] Me=methyl

[0217] Ms=mesyl=methanesulfonyl

[0218] OAc=acetate

[0219] Ph=phenyl

[0220] TFA=trifluoroacetic acid

[0221] THF=tetrahydrofaran

[0222] TMS=trimethylsilyl

EXAMPLE 11-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]tetrahydro-5-(hydroxymethyl)-2(1H)-pyrimidinone

[0223]

[0224] To a solution of 4-bromoaniline (1.72 g, 10.0 mmol) in THF (10mL) at room temperature under nitrogen, was added a solution of sodiumhexamethyldisilazide (22.0 mL, 1M in THF, 22 mmol) over 10 min. A darkbrown viscous solution formed. After 30 min, di-t-butyldicarbonate (2.4g, 11 mmol) was added in one portion. The reaction was stirred for 4 h,quenched with 10% citric acid solution and extracted twice with CH₂Cl₂.The extracts were combined, dried (Na₂SO₄) and evaporated under reducedpressure to provide a red-brown semi-solid. Purification by flashchromatography on silica gel (5×20 cm column, 42:58 CH₂Cl₂/hexanes) gave1A as a white solid, 1.73 g, (64% yield), mp 110-112° C. LC/MS gave thecorrect molecular ion [(M+H)⁺=272] for the desired compound.

[0225] B.

[0226] To a solution of 1A (1.58 g, 5.80 mmol) in DMF (3 mL) at roomtemperature under argon was added sodium hydride (240 mg, 60% mineraloil dispersion, 6.0 mmol) portionwise over 5 min. After 20 min more, theresulting light yellow solution was treated with ethyl 2-(bromomethyl)propenoate (1.0 mL, 7.25 mmol). A precipitate formed at once. After 10min, the reaction was quenched with saturated NH₄Cl solution andextracted twice with ether. The extracts were combined, dried (Na₂SO₄)and evaporated. Purification by flash chromatography on silica gel (5×20cm column, 3:1 CH₂Cl₂/hexanes) gave 1B as a colorless oil, 1.90 g, (85%yield). LC/MS gave the correct molecular ion [(M+H)⁺=384] for thedesired compound.

[0227] To a stirred solution of 1B (1.259 g, 3.28 mmol) in THF/EtOH(1:1, 8 mL) was added 2,4-dichlorobenzylamine (2.0 mL, 14.8 mmol) at 45°C. under argon. After 42 h, the reaction mixture was evaporated and theresidue purified by flash chromatography on silica gel (5×20 cm column,6:19 EtOAc/hexanes) to give the title compound as a colorless oil, 1.72g, (94% yield). LC/MS gave the correct molecular ion [(M+H)⁺=559] forthe desired compound.

[0228] A solution of 1C (364 mg, 0.65 mmol) in 4N HCl/dioxane (3 mL) wasstirred at room temperature under argon for 4 h. The solution wasevaporated and the residue partitioned between saturated NaHCO₃ solutionand EtOAc. The organic extract was dried (Na₂SO₄) and evaporated to give1D as a colorless oil, 299 mg, (100% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=459] for the desired compound. The material wasused without purification in the next reaction.

[0229] To a solution of 1D (299 mg, 0.65 mmol), triethylamine (212 μL,1.52 mmol) and DMAP (7 mg, 0.06 mmol) in CH₂Cl₂ (3 mL) at 0° C. underargon was added phosgene solution (355 μL, 1.98M in toluene, 0.70 mmol).The reaction mixture was stirred and warmed to room temperature. After24 h, the reaction was quenched with saturated NaHCO₃ solution andextracted three times with EtOAc. The organic extracts were combined,dried, evaporated and purified by flash chromatography on silica gel (5×15 cm column, 1:9:10 Et₂O/hexanes/CH₂Cl₂) to give 1E as a white solid,145 mg, (46% yield), mp 130-132° C. LC/MS gave the correct molecular ion[(M+H)⁺=485] for the desired compound.

[0230] To a solution of 1E (305 mg, 0.63 mmol) in CH₂Cl₂ (5 mL) at roomtemperature under argon, was added diisobutylaluminum solution (1.4 mL,1M in hexanes, 1.4 mmol). After 20 h, the reaction was treated withpotassium sodium tartrate (10 mL, 1M) solution and stirred 1 h. Thereaction mixture was extracted three times with dichloromethane. Theorganic extracts were combined, dried (MgSO₄) and evaporated. Theresidue was purified by flash chromatography on silica gel (5×15 cmcolumn, 11:9 EtOAc/hexanes ) to give the title compound 1 as a colorlessoil, 200 mg, (71% yield). LC/MS gave the correct molecular ion[(M+H)⁺=443] for the desired compound.

EXAMPLE 2 (Alternative Method)1-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]tetrahydro-5-(hydroxymethyl)-2(1H)-pyrimidinone

[0231]

[0232] To a stirred solution of 4-bromophenylisocyanate (4.95 g, 25.0mmol) in CH₂Cl₂ (50 mL) at room temperature under N₂ was added asolution of 2,4-dichlorophenylmethylamine (3.36 mL, 25.0 mmol) in CH₂Cl₂(10 mL) over 5 min. The reaction warmed autogenously as a whiteprecipitate formed. After 2 h, the reaction was filtered, and thecollected solids were washed with hexanes and dried in vacuo (60° C.) togive 2A as a white solid, 9.23 g (99% yield), mp 220-223° C. LC/MS gavethe correct molecular ion [(M+H)⁺=373] for the desired compound.

[0233] To a stirred slurry of 2A (6.75 g, 18.0 mmol) in DMF (50 mL) atroom temperature under N₂ was added NaH (60% oil dispersion, 1.48 g,37.0 mmol) over 15 min. The slurry was heated to 50° C. and stirred for30 min. To the resulting mixture was added3-chloromethyl-3-chloro-1-propene (2.26 mL, 19.5 mmol) in one portion. Alight yellow precipitate formed. After 2 h, the reaction mixture wascooled to room temperature, quenched with 5% potassium hydrogen sulfatesolution and extracted twice with ether. The organic extracts werecombined, washed twice with water, once with brine, dried (MgSO₄) andevaporated. Purification by flash chromatography on silica gel (12.5×30cm column, CH₂Cl₂) provided 2B as a white solid, 6.10 g (80% yield), mp122-124° C. LC/MS gave the correct molecular ion [(M+H)⁺=425] for thedesired compound.

[0234] To a solution of 2B (2.13 g, 5.00 mmol) in THF (5 mL) at roomtemperature under argon, was added 9-BBN solution (11 mL, 0.5M in THF,5.5 mmol). The reaction mixture was heated to reflux. After 14 h, thereaction was cooled to room temperature and treated with aqueous sodiumhydroxide solution (2 mL, 3M) and then, cautiously, 30% hydrogenperoxide (2 mL) at a rate to keep the temperature below 40° C. Aftercooling to room temperature, the reaction was diluted with water andextracted twice with EtOAc. The organic extracts were combined, dried(MgSO₄) and evaporated. Recrystallization from EtOAc/hexanes gave thetitle compound 2 as a white solid, 2.03 g, (91% yield), mp 127-129° C.LC/MS gave the correct molecular ion [(M+H)⁺=443] for the desiredcompound.

EXAMPLE 31-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0235]

[0236] To a stirred solution of the title compound of Example 2 (204.5mg, 0.460 mmol), imidazole (70 mg, 1.03 mmol) and triphenylphosphine(121 mg, 0.461 mmol) in THF (2 mL) at room temperature under N₂ wasadded a solution of iodine (117 mg, 0.461 mmol) in THF (1 mL) over 5min. After 10 min, the light purple solution was quenched with 5% NaHSO₃solution and extracted twice with ether (5 mL). The extracts werecombined, dried (MgSO₄) and evaporated. Purification by flashchromatography on silica gel (5×7 cm column, CH₂Cl₂) gave 3A as acolorless oil, 190 mg (75% yield). LC/MS gave the correct molecular ion[(M+H)⁺=553] for the desired compound.

[0237] A stirred solution of 3A (190 mg, 0.35 mmol) and potassiumcyanide (80 mg, 1.2 mmol) in DMSO (2 mL) was heated at 50° C. under N₂for 8 h. The reaction mixture was cooled, added to water (20 mL) andextracted three times with ether (5 mL). The extracts were combined,washed with water and brine, dried (MgSO₄) and evaporated. Purificationby flash chromatography on silica gel (2.5×15 cm column, 1:49ether/CH₂Cl₂) gave 3B as a colorless oil, 131 mg (84% yield). LC/MS gavethe correct molecular ion [(M+H)⁺=452] for the desired compound.

[0238] A stirred solution of 3B (578 mg, 1.28 mmol) in ethanol (5 mL)and concentrated HCl (5 mL) was heated at reflux under N₂ for 24 h. Thereaction mixture was cooled, added to water (20 mL) and extracted twicewith CH₂Cl₂ (20 mL). The extracts were combined, washed with water,dried (MgSO₄) and evaporated. The residuum was dissolved in THF (5 mL)and stirred with sodium hydroxide solution (1M, 5 mL) for 1 h. Thereaction mixture was diluted with water (10 mL) and extracted twice withether (10 mL). The aqueous phase was treated with dilute hydrochloricacid (1M, 5.5 mL) and extracted twice with CH₂Cl₂. The extracts werecombined, dried (MgSO₄) and evaporated. Recrystallization(EtOAc/hexanes) provided the title compound 3 as a white solid, 499 mg(83% yield), mp 183-185° C. LC/MS gave the correct molecular ion[(M+H)⁺=471] for the desired compound.

[0239] Elemental analysis for C₁₉H₁₇N₂O₃BrCl₂

[0240] Calc. % C, 48.33; H, 3.63; N, 5.93; Br, 16.92; Cl, 15.01.

[0241] Fnd. C, 48.05; H, 3.56; N, 5.77; Br, 17.08; Cl, 15.15.

EXAMPLE 41-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetamide

[0242]

[0243] To a solution of the compound of Example 3 (23 mg, 0.049 mmol) inCH₂Cl₂ (1 mL) at room temperature under N₂ was added oxalyl chloridesolution (2M in CH₂Cl₂, 0.2 mL, 0.4 mmol) and then DMF (10 μL). After 2h, the solution was evaporated. To the resulting oil was added CH₂Cl₂ (2mL) and ammonium hydroxide (concentrated solution, 1 mL). After 1 h, thereaction was evaporated. Purification by flash chromatography on silicagel (2.5×7 cm column, 1:49 CH₃OH/EtOAc) and recrystallization(THF/hexanes) gave the title compound 4 as a white solid, 20 mg (87%yield), mp 167-169° C. LC/MS gave the correct molecular ion [(M+H)⁺=470]for the desired compound.

EXAMPLE 51-(4-Bromophenyl)-3-[[2,4-dichloro-3-(phenylmethyl)phenyl]methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0244]

[0245] To a solution of 2,4-dichlorobenzylamine (1.76 g, 10.0 mmol) inCH₂Cl₂ (20 mL) at room temperature under N₂ was addeddi-t-butyldicarbonate (2.18 g, 10.0 mmol). After 30 min, the solutionwas evaporated. Purification by flash chromatography on silica gel (5×15cm column, CH₂Cl₂) gave 5A as a colorless oil, 2.06 g (75% yield). LC/MSgave the correct molecular ion [(M+H)⁺=276] for the desired compound.

[0246] To a solution of 5A (748 mg, 2.71 mmol) in THF (5.5 mL) at −75°C. under N₂ was added n-BuLi solution (2.5M in hexanes, 2.50 mL, 6.2mmol) over 15 min. After 30 min, the deep orange solution was treatedwith a solution of benzaldehyde (0.33 mL, 3.2 mmol) in THF (1 mL) over 5min. The resulting thick gelatinous reaction mixture was allowed to warmto room temperature as a solution formed. After 1 h, the reaction wasquenched with 10% citric acid and extracted twice with EtOAc. Theorganic extracts were combined, dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (5×15 cm column, 1:39EtOAc/CH₂Cl₂) gave 5B as an amorphous white solid, 410 mg (40% yield).LC/MS gave the correct molecular ion [(M+H)⁺=382] for the desiredcompound.

[0247] 5B (286 mg, 0.75 mmol) was treated with HCl/dioxane (4N, 5 mL) atroom temperature under N₂ for 4 h. The solution was evaporated, theresidue dissolved in CH₂Cl₂ (10 mL) and stirred rapidly with saturatedNaHCO₃ solution. The organic phase was separated, dried (Na₂SO₄) andevaporated. The residue was dissolved in CH₂Cl₂ (5 mL) and treated with4-bromophenylisocyanate (140 mg, 0.7 mmol). After 10 min, the reactionmixture was evaporated. Purification by flash chromatography on silicagel (2.5×20 cm column, 1:7 EtOAc/CH₂Cl₂) gave 5C as an amorphous whitesolid, 235 mg (70% yield). LC/S gave the correct molecular ion[(M+H)⁺=479] for the desired compound.

[0248] To a stirred solution of 5C (152 mg, 0.317 mmol) in TFA (2 mL) atroom temperature under N₂ was added triethylsilane (160 μL, 1.0 mmol).After 1 h, the resulting slurry was treated with saturated NaHCO₃solution and the resulting solids filtered, washing with water and driedin vacuo to give 5D as a white solid, 145 mg (98% yield). LC/MS gave thecorrect molecular ion [(M+H)⁺=463] for the desired compound.

[0249] By using the method of Example 2 Part B, but with 5D (1.00 g,2.15 mmol), 5E was obtained as a white amorphous solid, 830 mg (75%yield). LC/MS gave the correct molecular ion [(M+H)⁺=515] for thedesired compound.

[0250] By using the method of Example 2 Part C, but with 5E (690 mg,1.34 mmol), 5F was obtained as a white amorphous solid, 465 mg (65%yield). LC/MS gave the correct molecular ion [(M+H)⁺=533] for thedesired compound.

[0251] By using the method of Example 3 Part A, but with 5F (445 mg,0.83 mmol), 5G was obtained as a white amorphous solid, 475 mg (89%yield). LC/MS gave the correct molecular ion [(M+H)⁺=643] for thedesired compound.

[0252] By using the method of Example 3 Part B, but with 5G (460 mg,0.714 mmol), 5H was obtained as a white amorphous solid, 310 mg (80%yield). LC/MS gave the correct molecular ion [(M+H)⁺=542] for thedesired compound.

[0253] By using the method of Example 3 Part C, but with 5H (300 mg,0.55 mmol), the title compound 5 was obtained as a white solid, 235 mg(76% yield), mp 174-176° C. LC/MS gave the correct molecular ion[(M+H)⁺=561] for the desired compound.

EXAMPLE 6[[1-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidinyl]methyl]phosphonicacid

[0254]

[0255] A.

[0256] A solution of 3A (346 mg, 0.624 mmol) in freshly distilledtriethylphosphite (4 mL) was heated at reflux under N₂ for 24 h. Thereaction mixture was then distilled at 100° C. at 0.5 Torr to removevolatile materials. Purification of the residuum by flash chromatographyon silica gel (2.5×15 cm column, EtOAc) gave 6A as a colorless oil, 275mg (67% yield). LC/MS gave the correct molecular ion [(M+H)⁺=563] forthe desired compound.

[0257] To a solution of 6A (315 mg, 0.481 mmol) in CH₂Cl₂ (5 mL) wasadded bromotrimethylsilane (0.20 mL, 1.5 mmol) at room temperature underN₂. After 24 h, the reaction mixture was evaporated and the residuumdissolved in EtOAc. The organic solution was washed three times withhydrochloric acid (3M), dried (MgSO₄) and partially evaporated. Hexaneswere added to the concentrated solution and the resulting white solidisolated and dried in vacuo to give the title compound 6, 225 mg (92%yield), mp >220° C. LC/MS gave the correct molecular ion [(M+H)⁺=507]for the desired compound.

[0258] Elemental analysis as C₁₈H₁₉N₂O₄BrCl₂P+0.25 H₂O+0.33 EtOAc

[0259] Calc. % C, 42.76; H, 4.11; N, 5.16; Br, 14.72; Cl, 13.06.

[0260] Fnd. C, 42.90; H, 3.73; N, 5.26; Br, 14.54; Cl, 12.73.

EXAMPLE 71-[(2,4-Dichlorophenyl)methyl]hexahydro-2-oxo-3-(2-phenoxyphenyl)-5-pyrimidineaceticacid

[0261]

[0262] To a stirred solution of 2-phenoxybenzoic acid (2.14 g, 10.0mmol) in CH₂Cl₂ (10 mL) at room temperature was added a solution ofoxalyl chloride (2M in CH₂Cl₂, 7 mL, 14 mmol) and then DMF (100 μL). Thesolution was stirred 1 h and then evaporated. The resulting oil wasdissolved in acetone (10 mL) and, at room temperature with rapidstirring, treated with a solution of sodium azide (2.5 g, 38 mmol) inwater (10 mL). After 20 min, the mixture was poured into ice water (50mL) and extracted three times with toluene (20 mL portions). The organicextracts were combined, dried (MgSO₄) and heated to reflux, using aDean-Stark trap to remove water. After 1 h, the resulting solution wascooled and treated with 2,4-dichlorobenzylamine (1.40 mL, 10.0 mmol).After 20 min, the slurry was evaporated and the residual solid suspendedin CH₂Cl₂. Filtration gave 7A as a white solid, 3.23 g (86% yield).LC/MS gave the correct molecular ion [(M+H)⁺=387] for the desiredcompound.

[0263] By using the method of Example 2 Part B, but with 7A (2.71 g,7.00 mmol), 7B was obtained as a white amorphous solid, 979 mg (32%yield). LC/MS gave the correct molecular ion [(M+H)⁺=439] for thedesired compound.

[0264] By using the method of Example 2 Part C, but with 7B (974 mg,2.22 mmol), 7C was obtained as a white amorphous solid, 598 mg (59%yield). LC/MS gave the correct molecular ion [(M+H)⁺=533] for thedesired compound.

[0265] By using the method of Example 3 Part A, but with 7C (590 mg,1.29 mmol), 7D was obtained as a white amorphous solid, 640 mg (87%yield). LC/MS gave the correct molecular ion [(M+H)⁺=567] for thedesired compound.

[0266] By using the method of Example 3 Part B, but with 7D (625 mg,1.10 mmol), 7E was obtained as a white amorphous solid, 446 mg (87%yield). LC/MS gave the correct molecular ion [(M+H)⁺=467] for thedesired compound.

[0267] By using the method of Example 3 Part C, but with 7E (167 mg,0..358 mmol), the title compound 7 was obtained as a light yellowamorphous solid, 161 mg (92% yield). LC/MS gave the correct molecularion [(M+H)⁺=485] for the desired compound.

[0268] Elemental analysis as C₂₅H₂₂N₂O₄Cl₂+1 H₂O

[0269] Calc. % C, 59.65; H, 4.81; N, 5.57; Cl, 14.09.

[0270] Fnd. C, 59.71; H, 4.49; N, 5.33; Cl, 14.04.

EXAMPLE 81-(4-Bromophenyl)-3-[(4-chlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0271]

[0272] To a stirred solution of 4-bromophenyl isocyanate (49.50 g, 250mmol) in CH₂Cl₂ (250 mL) at room temperature was added a solution of4-methoxyaniline (30.79 g, 250 mmol) in CH₂Cl₂ (250 mL) dropwise. Afteraddition, the reaction mixture was stirred at room temperature for 30minutes as a precipitate formed. The precipitate was filtered and washedwith CH₂Cl₂ (500 mL×2) to give 8A as a white solid, 77.01 g, (96%yield). LC/MS gave the correct molecular ion [(M+H)⁺=321] for thedesired compound.

[0273] To a stirred solution of lithium aluminum hydride (1M in THF, 270mL, 270 mmol) under nitrogen at room temperature was added a solution ofdiethyl allylmalonate (49.0 g. 245 mmol) in THF (30 mL) dropwise over 40min. The temperature was not allowed to rise above 50° C. The reactionmixture was stirred at room temperature for 5 h and quenched withsaturated sodium chloride (500 mL) at 0° C. and stirred for 30 min. Theslurry was filtered through Celite. The filtrate was extracted threetimes with EtOAc (300 mL), the organic extracts were combined, dried(Na₂SO₄) and evaporated to give 8B as a colorless oil, 24.0 g. (85%yield).

[0274] To a stirred solution of 8B (23.70 g, 174 mmol) in CH₂Cl₂ (360mL) under nitrogen at 0° C. was added triethylamine (53.4 mL, 343 mmol),and then methanesulfonyl chloride (28.3 mL, 364 mmol) dropwise. Thetemperature was not allowed to rise above 10° C. After addition, thereaction mixture was stirred at 0° C. for 2 h and diluted with CH₂Cl₂(400 mL). The reaction mixture was washed with 10% citric acid solution(400 mL), water (400 mL) and brine (400 mL), dried (Na₂SO₄) andevaporated to give 8C as a yellow oil, 52.02 g, (93% yield).

[0275] D.

[0276] To a stirred slurry of 8A (33.02 g, 103.4 mmol), NaOH (20.68 g,517 mmol) and tetrabutylammonium iodide (600 mg) in toluene (300 mL)under nitrogen at room temperature was added a solution of 8C (32.85 g,108.6 mmol) in toluene (50 mL). The reaction mixture was heated atreflux for 5 h. A clear solution was formed from the original slurry.After the reaction mixture was cooled to room temperature, CH₂Cl₂ (600mL) was added. The reaction mixture was washed with aqueous 5% KHSO₄(600 mL), H₂O (600 mL), saturated NaHCO₃ solution and brine (600 mL),dried (Na₂SO₄) and evaporated. Purification by flash chromatography onsilica gel (3:47 Et₂O/CH₂Cl₂) gave 8D as a yellow oil, 20 g, (48%yield). LC/MS gave the correct molecular ion [(M+H)⁺=401] for thedesired compound.

[0277] To a stirred cloudy suspension of 8D (13.6 g, 31.2 mmol) in MeOH(400 mL) and H₂O (200 mL), was added a solution of OsO₄ (2.5% intert-butyl alcohol, 3.1 mL). The reaction mixture was stirred undernitrogen at room temperature for 45 min. Sodium periodate (20.02 g, 93.6mmol) was added over 30 min and the reaction mixture was then stirredfor 5 h. Water (400 mL) was added to the reaction mixture and thenextracted three times with CH₂Cl₂ (300 mL). The organic extracts werecombined, washed twice with H₂O (300 mL), once with brine (300 mL);dried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (7:93 Et₂O/CH₂Cl₂) gave 8E as a white solid, 8.0 g, (65%yield). LC/MS gave the correct molecular ion [(M+H)⁺=403] for thedesired compound.

[0278] Ammonium persulfate (4.78 g, 20.96 mmol) was added portionwise tocold concentrated H₂SO₄ (6.2 mL, 116 mmol) under nitrogen at a rate suchthat the temperature was not allowed to rise above 15° C. The resultingsolution was added dropwise to a stirred suspension of 8E (3.25 g, 8.06mmol) in MeOH (25 mL) at 0° C. The reaction mixture was stirred at 0° C.for 2 h and stored at 5° C. overnight and then diluted with H₂O (100 mL)and extracted three times with CH₂Cl₂ (100 mL). The extracts werecombined, washed with saturated aqueous NaHCO₃ (100 mL), H₂O (100 mL)and brine (100 mL), dried (Na₂SO₄) and evaporated. Purification by flashchromatography on silica gel (1:9 Et₂O/CH₂Cl₂) gave 8F as a white solid,3.2 g, (92% yield). LC/MS gave the correct molecular ion [(M+H)⁺=433]for the desired compound.

[0279] To a stirred solution of ammonium cerium (IV) nitrate ((23.63 g,43.10 mmol) in H₂O (60 mL) at −10° C. was added a solution of 8F (6.225g, 14.37 mmol) in CH₃CN (100 mL) over 30 min. The reaction mixture wasstirred at −10° C. for 5 min and quenched with 10% aqueous sodiumacetate (500 mL). The reaction mixture was extracted three times withEtOAc (200 mL) and twice with CH₂Cl₂ (150 mL). The extracts werecombined, washed with 10% NaHSO₃ (300 mL), H₂O (300 mL) and brine (300mL), dried (Na₂SO₄) and evaporated. Purification by flash chromatographyon silica gel (100% EtOAc) gave 8G as a white solid, 2.58 g, (55%yield). LC/MS gave the correct molecular ion [(M+H)⁺=327] for thedesired compound.

[0280] To a stirred solution of 8G (98.4 mg, 0.3 mmol) in DMF (1.5 mL)under nitrogen at room temperature was added NaH (60% oil dispersion12.1 mg, 0.303 mmol) in one portion. The reaction mixture was stirred atroom temperature for 5 min and a solution of 4-chlorobenzyl chloride(53.2 mg, 0.33 mmol) in DMF (0.5 mL) was then added. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas diluted with H₂O (5 mL) and extracted three times with EtOAc (10mL). The extracts were combined, washed once each with H₂O, saturatedNaHCO₃ solution and brine, and then dried (Na₂SO₄) and evaporated.Purification by flash chromatography (1:19 Et₂O/CH₂Cl₂) gave 8H as awhite solid, 33.4 mg, (24% yield). LC/MS gave the correct molecular ion[(M+H)⁺=451] for the desired compound.

[0281] To a stirred solution of 8H (79.4 mg, 0.176 mmol) in MeOH (1.5mL) at room temperature was added aqueous NaOH solution (5M, 1.5 mL).The reaction mixture was stirred at room temperature overnight andconcentrated to about 1.5 mL. The residue was diluted with H₂O (4 mL)and acidified by adding HCl (1M) dropwise to pH 2. The reaction mixturewas extracted three times with CH₂Cl₂ (10 mL). The extracts werecombined, washed with H₂O and brine, and then dried (Na₂SO₄) andevaporated to give the title compound as a white foam, 40.0 mg, 52%yield. LC/MS gave the correct molecular ion [(M+H)⁺=437] for the desiredcompound.

EXAMPLE 91-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetichydroxamic acid

[0282]

[0283] To a stirred solution of compound 3C (194 mg, 0.2 mmol) in CH₂Cl₂(8 mL) under nitrogen at room temperature was added a solution of oxalylchloride (2M in CH₂Cl₂, 0.5 mL, 1 mmol) and DMF (1 drop). The reactionmixture was stirred for 1 h and evaporated. The residue was dissolved inCH₂Cl₂ (5 mL) and evaporated three times. The residue was dried in vacuofor 1 h to give 9A as a colorless oil.

[0284] To a stirred slurry of hydroxylamine hydrochloride (35 mg, 0.5mmol) and Et₃N (0.14 mL, 1.0 mmol) in CH₂Cl₂ (5 mL) under nitrogen atroom temperature was added a solution of 9A (98.2 mg, 0.2 mmol) inCH₂Cl₂ (5 mL) dropwise. The reaction mixture was stirred at roomtemperature overnight and then evaporated. Purification by preparativeHPLC gave the title compound 9 as a pink solid, 15.0 mg, (15% yield).LC/MS gave the correct molecular ion [(M+H)⁺=486] for the desiredcompound.

EXAMPLE 101-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]tetrahydro-5-(2-hydroxyethyl)-2(1H)-pyrimidinone

[0285]

[0286] To a stirred solution of compound 3C (90 mg, 0.19 mmol) in CH₂Cl₂(10 mL) under nitrogen at room temperature was added a solution ofoxalyl chloride (2M in CH₂Cl₂, 0.4 mL, 0.8 mmol) and DMF (1 drop). Thereaction mixture was stirred at room temperature for 1 h andconcentrated in vacuum. The residue was dissolved in CH₂Cl₂ (5 mL) andevaporated three times. The residue was dried in vacuo for 1 h and MeOH(10 mL) was added to the residue. The reaction mixture was stirred atroom temperature for 1 h and concentrated in vacuum to give 10A as anoil, 87.5 mg, (95% yield). LC/MS gave the correct molecular ion[(M+H)⁺=485] for the desired compound.

[0287] To a stirred solution of 10A (87 mg, 0.18 mmol) in CH₂Cl₂ (8 mL)under nitrogen at −78° C. was added a solution of diisobutylaluminumhydride (1M in CH₂Cl₂, 0.4 mL, 0.4 mmol) dropwise. The reaction mixturewas stirred at −78° C. for 30 min, and then slowly warmed to roomtemperature and stirred at room temperature overnight. The reactionmixture was quenched with 5% KHSO₄ and stirred at room temperature for 1h. The reaction mixture was extracted three times with CH₂Cl₂ (10 mL).The extracts were combined, washed with H₂O (10 mL) and brine (10 mL),dried (Na₂SO₄) and evaporated. Purification by flash chromatography onsilica gel (1:50 MeOH/CH₂Cl₂) gave the title compound 10 as a whitesolid, 23 mg, (28% yield). LC/MS gave the correct molecular ion[(M+H)⁺=457] for the desired compound.

EXAMPLE 111-(4-Bromophenyl)-3-[(2-chlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0288]

[0289] By using the method of Example 8 Part H, but with 2-chlorobenzylchloride, 11A was prepared as an oil, 230 mg, 70% yield.

[0290] By using the method of Example 8 Part I, but with 11A (157 mg,0.37 mmol), the title compound 11 was prepared as a colorless foam, 140mg (90% yield). LC/MS gave the correct molecular ion [(M+H)⁺=437] forthe desired compound.

EXAMPLE 121-(4-Bromophenyl)-3-[(4-fluorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0291]

[0292] To a stirred suspension of compound 8C (102.3 mg, 0.31 mmol) inTHF (8 mL) under nitrogen at room temperature was added a solution ofpotassium bis(trimethylsily)amide (0.5M in toluene, 0.66 mL, 0.33 mmol).After 5 min, a solution of 4-fluorobenzylchloride (50 mg, 0.34 mmol) inTHF (0.5 mL) was added, followed by tetrabutylammonium iodide (115.6 mg,0.31 mmol). The reaction mixture was stirred under nitrogen at roomtemperature for 1 h and quenched with 5% aqueous Na₂SO₃. To the reactionwas added NaOH (1N, 1.5 mL) and the mixture was stirred at roomtemperature overnight. The reaction mixture was acidified to pH 2 byadding HCl (1M) dropwise at 0° C. and then extracted with CH₂Cl₂ (20mL). The extract was evaporated. Purification by CUQAX13M6-HY ionexchange resin gave the title compound 12 as a foam, 57.5 mg, 36.5%yield. LC/MS gave the correct molecular ion [(M+H)⁺=421] for the desiredcompound.

EXAMPLE 13 1-(4-Bromophenyl)-3-[(2-fluorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid

[0293]

[0294] To a mechanically agitated suspension of compound 8G (51.0 mg,0.16 mmol) and tetrabutylammonium iodide (57.6 mg, 0.16 mmol) in THF (1mL) under nitrogen at room temperature was added a solution of potassiumbis(trimethylsily)amide (0.5M in toluene, 0.36 mL, 0.18 mmol). After 5min, a solution of 2-fluorobenzylchloride (27.1 mg, 0.19 mmol) in THF(0.5 mL) was added. The reaction mixture was agitated under nitrogen atroom temperature for 1.5 h and then added to a solution of potassiumtrimethylsilanolate (40 mg, 0.31 mmol) in THF (0.4 mnL). After 16 h, thereaction mixture was quenched with 2% trifluoroacetic acid in MeOH (2mL) and evaporated. CH₂Cl₂ (4 mL) was added and a precipitate formed.The precipitate was filtered and the filtrate was evaporated.Purification of the filtrate residue by CUQAX13M6-HY ion exchangechromatography gave the title compound 13 as a foam, 30.0 mg, 46% yield.LC/MS gave the correct molecular ion [(M+H)⁺=421] for the desiredcompound.

EXAMPLES 14-51

[0295] The title compounds were prepared as part of a solution phaselibrary run using the following procedure.

[0296] To a suspension of Example 8 part G compound (80.0 mg, 0.24 mmol)and tetrabutylammonium iodide (90.3 mg, 0.24 mmol) in THF (1.5 mL) undernitrogen at room temperature was added a solution of potassiumbis(trimethylsilyl)amide (0.5M in toluene, 0.56 mL, 0.28 mmol). After 5min, a solution of RX (0.29 mmol) in THF (0.6 mL) was added. Thereaction mixture was shaken in a nitrogen atmosphere at room temperaturefor 1.5 h. To the reaction mixture was added a solution of potassiumtrimethylsilanolate (63 mg, 0.49 mmol) in THF (0.6 mL) and the mixturewas agitated at room temperature overnight. 2% CF₃COOH in MeOH (3.4 mL)was added and the reaction mixture was agitated at room temperature for30 min. The reaction mixture was filtered and the filtrate wasevaporated. CH₂Cl₂ (4 mL) was added and filtered through Celite. Thefiltrate was evaporated and the resulting crude product was purified bythe procedure outlined below.

[0297] 1) The CUQAX13M6-HY cartridge was conditioned with MeOH (10 mL×2)and 1:1 MeOH/CH₂Cl₂ (10 mL);

[0298] 2) The crude product was dissolved in CH₂Cl₂ (2 mL) and loadedonto a CUQAX13M6-HY cartridge;

[0299] 3) The cartridge was washed with CH₂Cl₂ (10 mL), CH₂Cl₂/MeOH (50MeOH, 10 mL) and MeOH (10 mL)

[0300] 4) The product was eluted with a solution of 2% CF₃COOH in MeOH.

[0301] The final fraction containing product was concentrated andpurified by ative HPLC to afford the title compound. Mass spectrometricand HPLC data collected for all compounds

[0302] Following the above procedure, the following compounds of theinvention were prepared: (M + H) positive Ex. X—R Structure Name ions 14

1-([1,1′-Biphenyl]-2- ylmethyl)-3-(4-bromo- phenyl)hexahydro-2-oxo-5-pyrimidineacetic acid 479 15

1-(4-Bromophenyl)-3-[(3- chloro-2-fluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 455 16

1-(4-Bromophenyl)-3- [(2,3-dichlorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 472 17

1-(4-Bromophenyl)-3- [(2,4-difluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 439 18

1-(4-Bromophenyl)-3- [(3,5-difluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 439 19

1-(4-Bromophenyl)-3- [(3,4-difluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 439 20

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2-[phenylsulfonyl)methyl]phenyl]methyl]-5- pyrimidineacetic acid 557 21

1-(4-Bromophenyl)-3-[(6- chloro-1,3-benzodioxol-5-yl)methyl]hexahydro-2- oxo-5-pyrimidineacetic acid 481 22

1-(4-Bromophenyl)- hexahydro-3-(2- naphthalenylmethyl)-2-oxo-5-pyrimidineacetic acid 453 23

1-(4-Bromophenyl)-3- [(3,4-dichlorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 472 24

1-(4-Bromophenyl)-3-[(2- methylphenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 417 25

1-(4-Bromophenyl)- hexahydro-3-[(2- iodophenyl)methyl]-2-oxo-5-pyrimidineactic acid 529 26

1-(4-Bromophenyl)-3-[(2- chloro-6-fluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 455 27

1-(4-Bromophenyl)-3-[(3- chlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 437 28

1-(4-Bromophenyl)-3- [(2,6-dichlorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 472 29

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[4-(trifluoromethyl)phenyl]methyl]-5-pyrimidineacetic acid 471 30

1-(4-Bromophenyl)-3- [(2,6-difluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 439 31

1-(4-Bromophenyl)- hexahydro-3-[(4-methyl- phenyl)methyl]-2-oxo-5-pyrimidineacetic acid 417 32

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2-(trifluoromethyl)phenyl]methyl]-5-pyrimidineacetic acid 471 33

1-(4-Bromophenyl)-3-[(2- bromophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 481 34

1-(4-Bromophenyl)- hexahydro-3-[(2-methoxy- phenyl)methyl]-2-oxo-5-pyrimidineacetic acid 433 35

1-(4-Bromophenyl)-3- [(2,5-difluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 439 36

1-(4-Bromophenyl)-3-[(4- cyanophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 428 37

1-(4-Bromophenyl)-3-[(2- cyanophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 428 38

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[3-(trifluoromethyl)phenyl]methyl]-5-pyrimidineacetic acid 471 39

1-(4-Bromophenyl)-3-[(3- fluorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 421 40

1-(4-Bromophenyl)-3-[(3- cyanophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 428 41

1-(4-Bromophenyl)-3-[[2- fluoro-5-(trifluoromethyl)-phenyl]methyl]hexahydro- 2-oxo-5-pyrimidineacetic acid 489 42

1-(4-Bromophenyl)-3-[[4- fluoro-2-(trifluoromethyl)-phenyl]methyl]hexahydro- 2-oxo-5-pyrimidineacetic acid 489 43

1-(4-Bromophenyl)-3-[[4- fluoro-3-(trifluoromethyl)-phenyl]methyl]hexahydro- 2-oxo-5-pyrimidineacetic acid 489 44

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[4-(phenylmethoxy)phenyl]methyl]-5-pyrimidineacetic acid 509 45

1-(4-Bromophenyl)-3- [(2,5-dimethylphenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 431 46

1-(4-Bromophenyl)-3- [(2,5-dichlorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 472 47

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[(2,4,5- trimethylphenyl)methyl]-5-pyrimidineacetic acid 445 48

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2-(trifluoromethoxy)phenyl]methyl]-5-pyrimidineacetic acid 487 49

1-(4-Bromophenyl)-3-[[2- fluoro-6-(trifluoromethyl)-phenyl]methyl]hexahydro- 2-oxo-5-pyrimidineacetic acid 489 50

1-(4-Bromophenyl)- hexahydro-3-[(4-methoxy- phenyl)methyl]-2-oxo-5-pyrimidineacetic acid 433 51

1-(4-Bromophenyl)-3-[(2- chloro-4-fluorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 455

EXAMPLE 521-(4-Bromophenyl)-3-[[2,4-dichloro-6-(phenylmethoxy)phenyl]methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0303]

[0304] To a solution of 2,4-dichloro-6-hydroxy benzaldehyde (1.87 g,10.0 mmol) in DMF (10 mL) at room temperature under N₂ was added sodiumhydride (60% oil dispersion, 440 mg, 11 mmol). After 20 min, benzylbromide (1.40 mL, 12 mmol) was added to the yellow solution. Thereaction mixture was heated to 50° C. for 16 h, then cooled to roomtemperature and then quenched with 5% KHSO₄ solution. The resultingsolids were collected, washed with water and dissolved in CH₂Cl₂. Thesolution was dried (MgSO₄) and partially evaporated. Addition of hexanesand filtration gave 52A as a white solid, 2.10 g (75% yield). LC/MS gavethe correct molecular ion [(M+H)⁺=281] for the desired compound.

[0305] To a solution of 52A (562 mg, 2.00 mmol) in THF (5 mL) at 0° C.under N₂ was added lithium borohydride solution (2M in THF, 0.3 mL, 2.4meq) over 1 min. After 15 min, the solution was warmed to roomtemperature. After an additional 30 min, the reaction was quenched withsaturated NaHCO₃ solution and extracted once with ether and once withCH₂Cl₂. The organic extracts were combined, dried (MgSO₄) and evaporatedto give 52B as a colorless oil, 548 mg (97% yield). LC/MS gave thecorrect molecular ion [(M+Na)⁺=305] for the desired compound.

[0306] To a stirred solution of 52B (546 mg, 1.92 mmol) in CH₂Cl₂ (5 mL)at room temperature was added a solution of PBr₃ (1M in CH₂Cl₂, 1.05 mL,3.15 meq) over 20 min. After 14 h, the reaction mixture was quenchedwith saturated NaHCO₃ solution and extracted twice with CH₂Cl₂. Theorganic extracts were combined, dried (Na₂SO₄/K₂CO₃) and evaporated togive 52C as an amorphous white solid, 654 mg (98% yield).

[0307] To a stirred solution of compound 8G (196 mg, 0.60 mmol) in THF(4 mL) at room temperature under N₂ was added potassiumhexamethyldisilazide solution (0.5M in toluene, 1.3 mL, 0.65 mmol).After 30 min, the resulting solution was treated with 52C (228 mg, 0.66mmol) and tetrabutylammonium iodide (244 mg, 0.66 mmol). The reactionmixture was stirred 14 h, quenched with 5% KHSO₄ solution and extractedtwice with EtOAc. The extracts were combined, dried (MgSO₄) andevaporated. Purification by flash chromatography gave 52D as a whiteamorphous solid, 120 mg (34% yield). LC/MS gave the correct molecularion [(M+H)⁺=591] for the desired compound.

[0308] By using the method of Example 8 Part I, but with 52D (110 mg,0.19 mmol), the title compound 52 was prepared as a white solid, 98 mg(89% yield). LC/MS gave the correct molecular ion [(M+H)⁺=577] for thedesired compound.

[0309] Elemental analysis for C₂₆H₂₃N₂O₄BrCl₂+0.32 H₂O.

[0310] Calc. % C, 53.47; H, 4.08; N, 4.80.

[0311] Fnd. C, 53.47; H, 4.13; N, 4.61.

EXAMPLE 531-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-α-hydroxy-2-oxo-5-pyrimidineaceticacid

[0312]

[0313] To a solution of pyridine (1.94 mL, 24 mmol) in CH₂Cl₂ (30 mL) at5° C. under N₂ was added chromium trioxide (1.20 g, 12 mmol). Theresulting red-orange solution was warmed to room temperature over 20 minand then a solution of compound 2C (896 mg, 2.02 mmol) in 5:1 CH₂Cl₂/DMF(6 mL) was added as a steady stream. After 15 min, the supernatantsolution was decanted from gummy solids. The solids were washed threetimes with ether. The organic extracts were combined and evaporated. Theresiduum was dissolved in ether and washed once with 5% NaHSO₃ solution.The organic phase was dried (MgSO₄) and evaporated. Purification byflash chromatography on silica gel (5×12 cm column, 3:97 ether/CH₂Cl₂)gave 53A as a white solid, 397 mg (44% yield), mp 138.5-140.5° C. LC/MSgave the correct molecular ion [(M+H)⁺=441] for the desired compound.

[0314] To a solution of 53A (221 mg, 0.5 mmol) in CH₂Cl₂ (1 mL) under N₂at room temperature was added trimethylsilylcyanide (67 μL, 0.5 mmol)and zinc iodide (1 mg, 0.003 mmol). After 16 h, the reaction mixture wasquenched with water and extracted twice with CH₂Cl₂. The extracts werecombined, dried (MgSO₄) and evaporated. The amorphous white residue wasdissolved in 1:1 concentrated HCl/TFA (2 mL) and heated to 110° C. for 8h. The reaction mixture was cooled and diluted with water. The resultinggummy solids were filtered, air-dried and recrystallized fromEtOAc/hexanes to give the title compound 53 (a mixture of diastereomers)as an amorphous white solid, 93 mg (38% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=487] for the desired compound.

EXAMPLE 541-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-5-hydroxy-2-oxo-5-pyrimidineaceticacid

[0315]

[0316] To a stirred solution of compound 2B (1.20 g, 2.82 mmol) inCH₂Cl₂ (100 mL) at −78° C. was bubbled 2% ozone/oxygen from a commercialozonizer. After 10 min, a bright blue solution had formed. Excess ozonewas purged with a nitrogen stream, the nearly colorless solution wasthen treated with triphenylphosphine (1.0 g, 3.8 mmol) and the mixturewarmed to room temperature. After 1 h, the solution was evaporated.Purification of the residual solids by flash chromatography on silicagel (5×20 cm column, 1:399 ether/CH₂Cl₂) gave 54A as a white solid, 895mg (74% yield), mp 128-130° C. LC/MS gave the correct molecular ion[(M+H)⁺=427] for the desired compound.

[0317] To a solution of lithium hexamethyldisilazide (1M in THF, 1.03mL, 1.03 mmol) in THF (1 mL) at −78° C. under N₂ was added EtOAc (100μL, 1.0 mmol) over 5 min. After 15 min, a solution of 54A (425 mg, 1.0mmol) in THF (2 mL) was added over 10 min. After an additional 10 min,hydrochloric acid (3N, 0.35 mL) was added rapidly and the reactionmixture was warmed to room temperature. The resulting yellow solutionwas partitioned between EtOAc and brine. The organic extract was dried(MgSO₄) and evaporated. Purification by flash chromatography on silicagel (5×15 cm column, 9:91 ether/CH₂Cl₂) gave 54B as a colorless oil, 326mg (64% yield). LC/MS gave the correct molecular ion [(M+H)⁺=515] forthe desired compound.

[0318] To a solution of 54B (320 mg, 0.62 mmol) in THF (2 mL) was addedsodium hydroxide solution (1M, 1 mL, 1 mmol) at room temperature underN₂. After 18 h, the reaction was quenched with 10% citric acid solutionand partially evaporated to remove THF. The resulting precipitate wasfiltered, washed with water and dried in vacuo to give the titlecompound 54 as a white solid, 290 mg (96% yield), mp 206-207° C. LC/MSgave the correct molecular ion [(M+H)⁺=487] for the desired compound.

[0319] Elemental analysis for C₁₉H₁₇N₂O₄BrCl₂.

[0320] Calc. % C, 46.75; H, 3.51; N, 5.74; Br, 16.37; Cl, 14.53.

[0321] Fnd. C, 46.76; H, 3.59; N, 5.61; Br, 16.44; Cl, 14.28.

EXAMPLE 551-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidinecarboxylicacid

[0322]

[0323] To a stirred solution of compound 2C (100 mg, 0.22 mmol), inacetone (2 mL) at room temperature under N₂ was added a solution ofJones reagent until an orange color persisted (120 μL, 0.32 mmol). After10 min, the light orange solution was quenched with 2-propanol anddiluted with equal volumes of ethyl acetate and water. The layers wereequilibrated, the organic fraction dried (MgSO₄) and evaporated.Purification by trituration with hot hexanes followed by triturationwith cold chloroform gave the title compound 55 as a white solid, 50 mg(49% yield), mp 229-232 C. LC/MS gave the correct molecular ion[(M+H)⁺=457] for the desired compound.

[0324] Elemental analysis for C₁₈H₁₅N₂O₃Cl₂Br+0.6 CHCl₃:

[0325] Calc. C, 42.17; H, 2.97; N, 5.29.

[0326] Fnd: C, 42.43; H, 2.97; N, 5.29.

EXAMPLE 561-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]tetrahydro-5-(1H-tetrazol-5-yl)-2(1H)-pyrimidinone

[0327]

[0328] To a stirred solution of compound 55A (650 mg, 1.41 mmol) inCH₂Cl₂ (5 mL) at room temperature was added oxalyl chloride solution (2Min CH₂Cl₂, 1.0 mL, 2 mmol) and DMF (50 μL). After 1 h, the reactionmixture was evaporated and the residuum was dissolved in THF (5 mL). Thesolution was cooled to 0° C. under N₂ and treated with an ammoniasolution (0.5M in dioxane, 6 mL, 3 mmol) over 10 min. After 1 h, thereaction was quenched with saturated NaHCO₃ solution and extracted twicewith EtOAc. The organic extracts were combined, dried (MgSO₄) andevaporated to give 56A as a tan solid, 412 mg (64% yield). LC/MS gavethe correct molecular ion [(M+H)⁺=456] for the desired compound.

[0329] To a stirred solution of 56A (397 mg, 0.868 mmol) in THF (5 mL)at room temperature under N₂ was added pyridine (145 μL, 1.74 mmol) andtrifluoroacetic anhydride (180 μL, 1.28 mmol). The reaction mixture wasrefluxed for 20 h, then cooled, quenched with hydrochloric acid (1M, 10mL) and extracted twice with EtOAc. The organic extracts were combined,dried (MgSO₄) and evaporated. Purification by flash chromatography onsilica gel (2.5×15 cm column, 2:123 ether/CH₂Cl₂) gave 56B as a whiteamorphous solid, 310 mg (81% yield). LC/MS gave the correct molecularion [(M+H)⁺=438] for the desired compound.

[0330] To a stirred solution of 56B (100 mg, 0.23 mmol) in toluene (2mL) at room temperature under N₂ was added azidotrimethyltin (70 mg,0.34 mmol). The reaction mixture was refluxed for 20 h, then cooled,quenched with methanol and evaporated. Purification by flashchromatography on silica gel (2.5×15 cm column, 1:19:182HOAc/MeOH/CH₂Cl₂) gave the title compound 56 as a white solid, 79 mg(71% yield), mp 207-209° C. LC/MS gave the correct molecular ion[(M+H)⁺=481] for the desired compound.

EXAMPLE 571-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]tetrahydro-5-(1H-tetrazol-5-ylmethyl)-2(1H)-pyrimidinone

[0331]

[0332] To a stirred solution of compound 3B (245 mg, 0.543 mmol) intoluene (2 mL) at room temperature under N₂ was added azidotrimethyltin(180 mg, 0.87 mmol). The reaction mixture was refluxed for 48 h, thencooled, quenched with methanol and evaporated. Purification by flashchromatography on silica gel (2.5×15 cm column, 1:13:186HOAc/MeOH/CH₂Cl₂) gave the title compound 57 as a white solid, 114 mg(42% yield), mp 155-157° C. LC/MS gave the correct molecular ion[(M+H)⁺=495] for the desired compound.

EXAMPLE 58(Z)-2-[1-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidinylidene]aceticacid And(E)-2-[1-(4-Bromophenyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidinylidene]aceticacid

[0333]

[0334] To a stirred solution of compound 54A (310 mg, 0.724 mmol) in THF(2 mL) at room temperature under N₂ was added ethyl(triphenylphosphoranylidene) acetate (280 mg, 0.80 mmol). After 40 h,the reaction mixture was evaporated. Purification of the residuum byflash chromatography on silica gel (2.5×15 cm column, 1:49 ether/CH₂Cl₂)gave 58A as a colorless oil, 2:3 ratio of cis/trans isomers, 277 mg (77%yield), mp 155-157° C. LC/MS gave the correct molecular ion [(M+H)⁺=497]for the desired compound.

[0335] To a stirred solution of 58A (270 mg, 0.54 mmol) in THF (2 mL) atroom temperature under N₂ was added sodium hydroxide solution (1 M, 1mmol). After 14 h, the reaction mixture was diluted with water (5 mL)and extracted twice with ether. The aqueous phase was brought to pH 2with hydrochloric acid (1M). The resulting solid was filtered, washedwith water and dried in vacuo to give the title compound 58 as anamorphous white solid, 2:3 ratio of cis/trans isomers, 260 mg (100%yield). LC/MS gave the correct molecular ion [(M+H)⁺=469] for thedesired compound.

EXAMPLE 591-[(2,4-Dichlorophenyl)methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5,5-pyrimidinediaceticacid

[0336]

[0337] A.

[0338] To a stirred solution of ethyl cyanoacetate (5.65 g, 50 mmol) inCH₃CN (50 mL) at −5° C. under argon was added a solution of1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 15.1 mL, 103 mmol) in CH₃CN(15mL) dropwise over 20 min. After addition was complete, allyl bromide(9.0 mL, 105 mmol) was added immediately and the reaction was stirredfor 30 min and then refluxed for 1 h. After cooling to room temperature,the reaction mixture was evaporated and the residue partitioned between3N HCl (30 mL) and EtOAc (100 mL). The organic extract was dried (MgSO₄)and evaporated. Purification by flash chromatography on silica gel (2:1CH₂Cl₂/hexanes as elutant) provided 59A as a colorless oil, 7.96 g(82%). LC/MS gave the correct molecular ion [(M+Na)⁺=216] for thedesired compound.

[0339] To a stirred solution of 59A (7.89 g, 40.8 mmol) in THF (40 mL)at room temperature under argon was added sodium hydroxide solution (1M,42 mL, 42 mmol). After 14 h, the solution was treated with potassiumhydrogen sulfate (7.5 g, 70 mmol) and evaporated to near dryness. Theresidue was agitated with CH₂Cl₂ (100 mL) and the solution was filteredthrough MgSO₄. Evaporation gave 59B as a crystalline white solid, 6.75 g(100%), mp 42-44° C.

[0340] To a stirred solution of 59B (888 mg, 5.37 mmol) in CH₂Cl₂ (100mL) at room temperature under argon was added oxalyl chloride indichloromethane (2M, 3.8 mL, 7.6 mmol) and DMF (100 μL). After 3 h, thereaction mixture was evaporated and the residue redissolved in CH₂Cl₂(10 mL). The resulting cloudy solution was added to a room temperaturesolution of p-toluidine (590 mg, 5.51 mmol) and triethylamine (1.5 mL,11 mmol) in CH₂Cl₂ (10 mL). After 3 h, the solution was diluted withadditional CH₂Cl₂ and washed with 5% KHSO₄ solution. The organicsolution was dried (MgSO₄) and evaporated. Purification by flashchromatography on silica gel (CH₂Cl₂ as elutant) provided 59C as a whitecrystalline solid, 1.21 g (89% yield), mp 69-71° C. LC/MS gave thecorrect molecular ion [(M+H)⁺=255] for the desired compound.

[0341] To a stirred solution of lithium aluminumhydride (1M in THF, 80mL, 80 mmol) at room temperature was added, portionwise over 5 min, 59C(8.95 g, 35.2 mmol). A clear solution formed as gas evolved. After 10min, a white opaque suspension formed, which was heated to reflux. After15 h, the reaction was cooled to room temperature, treated dropwise withsodium hydroxide solution (1M, 3.5 mL, 3.5 mmol) and stirred for 1 h.The resulting bulky solid was slurried in THF (100 mL) and the mixturewas heated to reflux for 1 h. After cooling, the solids were filtered,washing with THF. The filtrate was evaporated and then re-evaporatedfrom toluene to give 59D as a colorless oil, 8.22 g, (96% yield). LC/MSgave the correct molecular ion [(M+H)⁺=245] for the desired compound.

[0342] To a stirred solution of 59D (880 mg, 3.60 mmol) andtriethylamine (0.56 mL, 4.0 mmol) in CH₃CN (25 mL) at 5° C. undernitrogen was added a solution of carbonyl diimidazole (CDI, 292 mg, 1.8mmol) in CH₃CN (10 mL) over 20 min. After 1 h, solid CDI (292 mg, 1.8mmol) was added and, at 1 h intervals, additional CDI was added (150 mg,150 mg and 100 mg). After the last addition, the reaction mixture waswarmed to room temperature and stirred for 14 h. After evaporation, theresidue was partitioned between 5% potassium hydrogen sulfate solutionand EtOAc (200 mL). The organic extract was dried (MgSO₄) andevaporated. Purification by flash chromatography on silica gel (3:97CH₃OH/EtOAc) gave 59E as a white solid, 515 mg, (53% yield), mp 143-144°C. LC/MS gave the correct molecular ion [(M+H)⁺=271] for the desiredcompound.

[0343] To a stirred solution of 59E (500 mg, 1.85 mmol) in THF (10 mL)at room temperature under nitrogen was added a solution of potassiumhexamethyldisilazane (0.5M in toluene, 4.0 mL, 2.0 mmol) over 1 min.After 30 min, 2,4-dichlorobenzyl chloride (305 μL, 2.2 mmol) was added,followed by solid tetrabutylammonium iodide (810 mg, 2.2 mmol). After 14h, the reaction was quenched (5% KHSO₄) and extracted twice with EtOAc.The extracts were combined, washed with 10% NaHSO₃, dried (MgSO₄) andevaporated. Purification by flash chromatography on silica gel (2:1hexanes/EtOAc) gave 59F as a colorless oil, 785 mg, (99% yield). LC/MSgave the correct molecular ion [(M+H)⁺=430] for the desired compound.

[0344] To a solution of sodium hydroxide in methanol (2.5M, 55 mL, 138mmol) at room temperature was added a solution of 59F (5.86 g, 13.6mmol) in CH₂CO₂ (215 mL). The reaction flask was protected with aDrierite-filled tube and cooled to −74° C. The reaction mixture wastreated with a ˜2-3% O₃/O₂ mixture for 4 h (ozone addition was stoppedwhen LC/MS of an aliquot showed <5% of 59F remaining in the reactionmixture). The reaction was purged with nitrogen and then allowed to warmto room temperature overnight. The resulting solution was treated withhydrochloric acid (3 M, 46 mL, 138 mmol) and extracted twice withCH₂Cl₂. The combined extracts were evaporated, redissolved in CH₂Cl₂,dried (MgSO₄) and re-evaporated. The white foam product (6.42 g) wasdissolved in CH₂Cl₂ (˜40 mL) and treated with excess diazomethane inEt₂O. The excess diazomethane was dispersed with a nitrogen stream andthe reaction mixture dried (MgSO₄) and evaporated. The resulting oil wasagain dissolved in CH₂Cl₂ (˜30 mL) and stirred at room temperature withtriphenylphosphine (3.57 g, 13.6 mmol) for 30 min. Purification by flashchromatography on silica gel (CH₂Cl₂ followed by 1:19 Et₂O/CH₂Cl₂) gavea colorless oil (4.10 g), a mixture of aldehyde and methyl ester.

[0345] The oil was dissolved in THF (20 mL) and treated with sulfamicacid (1.10 g, 1.1 mmol) and H₂O (15 mL). After stirring 10 min, sodiumchlorite (80%, 1.28 g) in H₂O (5 mL) was added at room temperature.After 45 min, the reaction mixture was extracted twice with EtOAc. Theextracts were combined, dried (MgSO₄) and evaporated to give a lightyellow foam (4.42 g). The foam was dissolved in CH₂Cl₂ and treated asabove with ethereal diazomethane. Purification of the product by flashchromatography on silica gel (3:47 Et₂O/CH₂Cl₂) gave 59G as a colorlesssolid, 3.58 g, (57% yield). LC/MS gave the correct molecular ion[(M+H)⁺=494] for the desired compound.

[0346] To a stirred solution of 59G (3.80 g, 7.70 mmol) in THF (20 mL)under nitrogen at room temperature was added sodium hydroxide solution(1M, 20 mL, 20 mmol). The reaction mixture was heated at 50° C. for 4 h,cooled and partially evaporated to remove organic solvent. The aqueousremainder was acidified with hydrochloric acid (3M, 7 mL, 21 mmol). Theresulting solids were collected, washed with water and air-dried to give59H as a white solid, 3.24 g, (90% yield), mp 156-158° C. LC/MS gave thecorrect molecular ion [(M+H)⁺=465] for the desired compound.

EXAMPLE 601-(4-Bromophenyl)-3-[(4-chlorophenyl)methyl]hexahydro-2-oxo-5,5-pyrimidinediaceticacid anhydride

[0347]

[0348] A stirred solution of 59H (3.20 g, 6.9 mmol) was refluxed inacetic anhydride (15 mL) for 6 h under argon. After cooling to roomtemperature, the reaction mixture was evaporated and the residuedistilled trap-to-trap (110° C. @1 mm Hg) to remove the last traces ofacetic acid or anhydride. The residue provided 60 as a colorless glass,3.16 g (100%, ˜93% pure by NMR). LC/MS gave the correct molecular ion[(M+CH₃OH)⁺=478] for the desired compound.

EXAMPLES 61-146

[0349] The title compounds were prepared as part of a solution phaselibrary run using the following procedure.

[0350] To a solution of 60 compound (22 mg, 0.05 mmol) in CH₃CN (0.5 mL)under nitrogen

[0351] at room temperature was added a solution of RR′NH (0.15 mmol) inCH₃CN (0.5 mL). The reaction mixture was shaken in a nitrogen atmosphereat room temperature for 24 h. Each reaction was then diluted with waterto a volume of 2.0 mL and purified by preparative HPLC to afford thetitle compound. Mass spectrometric and HPLC data were collected for allcompounds.

[0352] Following the above procedure, the following compounds of theinvention were prepared: (M + H) positive Ex. Structure Name ion 61

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(phenyl- methyl)-amino]ethyl]-5- pyrimidineacetic acid 554 62

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- oxo-2-[4-(phenyl-methyl)-1-piperidinyl]-ethyl]-5- pyrimidineacetic acid 622 63

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- [[3-(1H-imidazol-1-yl)pro-pyl]-amino]-2-oxoethyl]-5- pyrimidineacetic acid 572 64

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(2-phenyl- ethyl)-amino]ethyl]-5- pyrimi-dineacetic acid 56865

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- [[2-(1H-indol-3-yl)ethyl]-amino]-2-oxoethyl]-5- pyrimidineacetic acid 607 66

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(2,3-dimethyl-cyclohexyl)-amino]-2-oxo- ethyl]hexahydro-3-(4- methyl-phenyl)-2-oxo-5-pyrimi-dineacetic acid 574 67

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- [[(1R,2R)-2-hydroxy-1- methyl-2-phenylethyl]-methylamino]-2-oxoethyl]- 5-pyrimidineacetic acid 612 68

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- oxo-2-[[3-(2-oxo-1-pyrroli-dinyl)propyl]amino]ethyl]-5- pyrimidineacetic acid 589 69

5-[2-(Cyclododecylamino)- 2-oxoethyl]-1-[(2,4- dichloro-phenyl)methyl]-hexahydro-3-(4- methylphenyl)-2-oxo-5- pyrimidineacetic acid 630 70

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [[(1S)-2-hydroxy-1-(phenylmethyl-)ethyl]- amino]-2-oxoethyl]-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 598 71

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-[(5-nitro-2-thiazolyl)amino]- 2-oxo-ethyl]-2-oxo-5- pyrimidine-acetic acid592 72

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[4-(2,3- dihydro-2-oxo-1H-benzimidazol-1-yl)-1- piperidinyl]-2-oxoethyl]- hexahydro-3-(4-methyl-phenyl)-2-oxo-5- pyrimidine-acetic acid 664 73

5-[2-[4-[(4-Chloro- phenyl)-phenylmethyl]- 1-piperazinyl]-2-oxo-ethyl]-1-[(2,4-dichloro- phenyl)methyl]-hexa- hydro-3-(4-methyl-phenyl)-2-oxo-5- pyrimidineacetic acid 734 74

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-[4-(phenylmethyl)-1- piperazinyl]-2-oxoethyl]- 5-pyrimidine-aceticacid 623 75

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[4-[2-oxo-2-(1- pyrrolidinyl)ethyl]-1- piperazinyl]ethyl]-5-pyrimidineacetic acid 644 76

5-[2-[[4-(5-Chloro-1,3- dihydro-1,3-dioxo-2H- isoindol-2-yl)-3-methyl-phenyl]amino]-2-oxoethyl]- 1-[(2,4-dichloro- phenyl)methyl]-hexahydro-3-(4-methyl-phenyl)-2-oxo- 5-pyrimi-dineacetic acid 734 77

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [2-(2-hydroxyethyl)-1-piperidinyl]-2-oxoethyl]- 3-(4-methylphenyl)-2- oxo-5-pyrimidineaceticacid 576 78

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- (4-hydroxy-4-phenyl-1-piperidinyl)-2-oxoethyl]- 3-(4-methylphenyl)-2- oxo-5-pyrimidineaceticacid 624 79

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-(2-hydroxyethyl)-1-piperidinyl]-2-oxoethyl]- 3-(4-methylphenyl)-2- oxo-5-pyrimidineaceticacid 576 80

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-[1-(phenylmethyl)-4- piperidinyl]-2-oxoethyl]- 5-pyrimidine-aceticacid 637 81

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-(octa-hydro-1(2H)- quinolinyl)-2-oxoethyl]-2- oxo-5-pyrimidineaceticacid 586 82

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- oxo-2-(4-oxo-1-phenyl- 1,3,8-triazaspiro-[4.5]decan-8-yl)ethyl]-5- pyrimidineacetic acid 678 83

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5-[2- oxo-2-[[3-(phenyl-meth-oxy)-phenyl]amino]-ethyl]- 5-pyrimidineacetic acid 646 84

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(4-phenoxy- phenyl)-amino]ethyl]-5- pyrimidine-acetic acid 63285

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[4-[[2- (diethyl-amino)ethoxy]-carbonyl]phenyl]amino]- 2-oxoethyl]-hexahydro- 3-(4-methyl-phenyl)-2-oxo-5-pyrimidine-acetic acid 683 86

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(1,2- diphenylethyl)amino]-2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid644 87

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]- amino]-2-oxoethyl]-3-(4- methyl-phenyl)-2-oxo-5-pyrimidin-eacetic acid 598 88

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[4- [(diethoxy-phosphinyl)-methyl]phenyl]-amino]- 2-oxoethyl]hexa-hydro- 3-(4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 690 89

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(3,3- diphenyl-propyl)amino]-2-oxoethyl]-hexahydro- 3-(4-methyl-phenyl)-2- oxo-5-pyrimidine-aceticacid 658 90

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [[3-(1-methylethoxy)-propyl]amino]-2- oxoethyl]-3-(4-methyl- phenyl)-2-oxo-5-pyrimidine-acetic acid 564 91

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(4-phenyl- butyl)-amino]ethyl]-5- pyrimidine-acetic acid 59692

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-(octyl-amino)-2- oxoethyl]-2-oxo-5- pyrimidineacetic acid 576 93

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[2- (dimethyl-amino)ethyl]-(phenyl-methyl)amino]- 2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 625 94

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(3,5-di- methoxyphenyl)amino]-2-oxoethyl]-hexahydro-3- (4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid600 95

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(2-phenyl- ethyl)-(phenylmethyl)- amino]ethyl]-5-pyri-midineacetic acid 658 96

5-[2-[[[3,5-Bis(trifluoro- methyl)phenyl]methyl]amino]-2-oxoethyl]-1-[(2,4- dichloro-phenyl)methyl]- hexahydro-3-(4-methyl-phenyl)-2-oxo-5- pyrimidineacetic acid 690 97

5-[2-[[2-[4-(Amino- sulfonyl)-phenyl]ethyl]- amino]-2-oxoethyl]-1-[(2,4-dichloro-phenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 647 98

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(1-ethyl- 1H-pyrazol-5-yl)amino]-2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid558 99

5-[2-[[2-[3,4-Bis(phenyl- methoxy)phenyl]ethyl]- amino]-2-oxoethyl]-1-[(2,4-dichloro- phenyl)methyl]hexahy- dro-3-(4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 780 100

5-[2-[(1H-Benzimidazol- 2-ylmethyl)amino]-2- oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 594 101

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[2-[5- (phenylmethoxy)-1H- indol-3-yl]ethyl]- amino]ethyl]-5-pyrimidine-acetic acid 713 102

1-[(2,4-Dichlorophenyl) methyl]-5-[2-(3,4- dihydro-6,7-dimethoxy-2(1H)-isoquino-linyl)-2- oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 640 103

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-(2-methoxyphenyl)-1-pipera-zinyl]-2-oxoethyl]- 3-(4-methylphenyl)-2- oxo-5-pyrimidineaceticacid 639 104

5-[2-(4-Cyano-4-phenyl- 1-piperidinyl)-2- oxoethyl]-1-[(2,4-dichloro-phenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 633 105

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[4-(phenyl- methoxy)-phenyl]- amino]ethyl]-5- pyrimidineaceticacid 646 106

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-(tricyclo- [3.3.1.13,7]-dec-1- ylamino)-2-oxoethyl]-5-pyrimidineacetic acid 598 107

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(1,1- dimethyl-ethyl)(2-hydroxyethyl)amino]-2- oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 564 108

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-[[3-(4-methyl-1-piperazinyl)- propyl]amino]-2- oxoethyl]-2-oxo-5-pyrimidineacetic acid 604 109

1-[(2,4-Dichlorophenyl)- methyl]-5-[2- [(2,2,3,3,4,4,4-heptafluorobutyl)amino]- 2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 646 110

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[3- (dimethyl-amino)propyl]-methylamino]-2- oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 563 111

5[2-[[2-[Bis(1- methylethyl)-amino]- ethyl]amino]-2-oxoethyl]-1-[(2,4-dichloro-phenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 591 112

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-[[3-[(phenylamino)- carbonyl]-phenyl]amino]- 2-oxoethyl]-5-pyrimi-dineacetic acid 659 113

5-[2-[(2,3-Dichloro- phenyl)[[4-(dimethyl- amino)phenyl]-methyl]-amino]-2-oxoethyl]-1- [(2,4-dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-2-oxo-5- pyrimidineacetic acid 742 114

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [[3-(hexahydro-1H-azepin-1-yl)propyl]- amino]-2-oxoethyl]-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 603 115

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [[1-methyl-2-(2-naphthalenyl-amino)-2- oxoethyl]amino]-2- oxoethyl]-3-(4-methylphenyl)-2-oxo-5- pyrimidineacetic acid. 661 116

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-[[(1-methyl-3-phenylpropyl)- (phenylmethyl)amino]-2- oxoethyl]-2-oxo-5-pyrimidineacetic acid 686 117

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[(1,1- dioxido-3-thienyl)amino]-2-oxoethyl]-hexahydro- 3-(4-methyl-phenyl)-2- oxo-5-pyrimi-dineaceticacid 582 118

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-hydroxy-4-(phenylmethyl)-1- piperidinyl]-2-oxoethyl]- 3-(4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 638 119

5-[2-[[4-[(2S)-2- (Acetylamino)-3- methoxy-3- oxopropyl]phenyl]amino]-2-oxoethyl]-1-[(2,4- dichlorophenyl)methyl]- hexahydro-3-(4-methylphenyl)-2-oxo-5- pyrimidineacetic acid 683 120

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[ethyl(4- pyridinylmethyl)amino]-2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid583 121

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[3-(2-phenyoxy- ethoxy)phenyl]amino]- ethyl]-5-pyrimidineacticacid 676 122

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[4-[(5- phenoxy- pentyl)oxy]phenyl]amino]- ethyl]-5-pyrimidineacetic acid 718 123

5-[2-[Bis(1,3- dimethylbutyl)amino]-2- oxoethyl]-1-[(2,4-dichlorophenyl)methyl]- hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 632 124

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[(1,2- diphenylethyl)methylamino]-2-oxoethyl]hexa- hydro-3-(4-methyl- phenyl)-2-oxo-5- pyrimidineaceticacid 658 125

5-[2-[4-(Cyanophenyl- methyl)-1-piperidinyl]-2- oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 647 126

5-[2-[4-[Bis(4-fluoro- phenyl)-methyl]-1- piperazinyl]-2-oxoethyl]-1-[(2,4-dichloro-phenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 735 127

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[4-(1- phenylethyl)-1- piperazinyl]ethyl]-5- pyrimidineaceticacid 637 128

5-[2-[7-(Aminosulfonyl)- 6-chloro-2,3-dihydro- 1,1-dioxido-4H-1,2,4-benzothiadiazin-4-yl]-2- oxoethyl]-1-[(2,4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 745 129

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[(3-phenoxy- phenyl)-amino]ethyl]-5- pyrimi-dineacetic acid 632130

5-[2-[[4-(4-Chloro- phenoxy)-phenyl]- amino]-2-oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]-hexahydro-3-(4- methyl-phenyl)-2-oxo-5-pyrimidine-acetic acid 667 131

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-hydroxy-4-[3-(trifluoro-methyl)phenyl]- 1-piperidinyl]-2- oxoethyl]-3-(4-methyl-phenyl)-2-oxo-5-pyrimi- dineacetic acid 692 132

5-[2-[[4-[(Benzoyl- amino)-sulfonyl]phenyl]- amino]-2-oxoethyl]-1-[(2,4-dichloro-phenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 723 133

5-[2-([1,1′-Biphenyl]-3- ylamino)-2-oxoethyl]-1- [(2,4-dichlorophenyl)-methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5- pyrimidineacetic acid 616134

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[4-(phenyl- methyl)-phenyl]amino]- ethyl]-5-pyrimidineaceticacid 630 135

5-[2-[[(2-Chloro-6- phenoxyphenyl)methyl]- amino]-2-oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 681 136

5[2-[4-(4- Chlorobenzoyl)-1- piperidinyl]-2-oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]-hexahydro-3-(4- methyl-phenyl)-2-oxo-5-pyrimidine-acetic acid 671 137

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-5-[2-[4-(1-naphthalenyl)-1- piperazinyl]-2-oxoethyl]- 2-oxo-5-pyrimidineaceticacid 659 138

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[4-(3-phenyl-2- propenyl)-2-pipera- zinyl]ethyl]-5-pyrimi-dineacetic acid 649 139

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-[2-(2-hydroxy-ethoxy)ethyl]-1-pipe- razinyl]-2-oxoethyl]-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 621 140

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-[2-oxo-2-[[2-(4- phenoxyphenyl)- ethyl]amino]ethyl]-5- pyrimidineaceticacid 660 141

5-[2-[4-[(Acetylamino)- methyl]-4-phenyl-1- piperidinyl]-2-oxoethyl]-1-[(2,4-dichlorophenyl)- methyl]hexahydro-3-(4- methylphenyl)-2-oxo-5-pyrimidineacetic acid 679 142

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[4-[2- (dimethylamino)ethyl]-1-piperazinyl]-2- oxoethyl]hexa-hydro-3- (4-methylphenyl)-2-oxo-5-pyrimidineacetic acid 604 143

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-5-[2- [4-(hydroxymethyl)-1-piperidinyl]-2-oxoethyl]- 3-(4-methylphenyl)-2- oxo-5-pyrimidineaceticacid 562 144

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(4-methylphenyl)-5-[2-[4-[2- (4-morpholinyl)ethyl]-1-piperazinyl]-2-oxoethyl]- 2-oxo-5-pyrimidineacetic acid 646 145

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[[6-[[(1,1-dimethylethoxy)carbonyl]- amino]hexyl]amino]-2- oxoethyl]hexahydro-3-(4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid 663 146

1-[(2,4-Dichlorophenyl)- methyl]-5-[2-[ethyl(4- phenoxyphenyl)amino]-2-oxoethyl]hexahydro-3- (4-methylphenyl)-2-oxo- 5-pyrimidineacetic acid660

EXAMPLE 1473-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetic acid

[0353]

[0354] To a stirred solution of ethylene glycol (22.4 mL, 0.4 mol)in THF(200 mL) at 0° C. under argon was added sodium hydroxide (60% oildispersion, 8.0 g, 0.2 mol) in portions over 30 min. The reactionmixture was warmed to room temperature and stirred overnight. To theresulting slurry was added a solution of t-butylchlorodiphenylsilane(52.0 mL, 0.2 mol) in THF (15 mL) in one portion. The reactiontemperature rose to 35° C. before subsiding to room temperature. After 1h, the reaction mixture was diluted with water (200 mL) and extractedthree times with hexane (100 mL portions). The organic extracts werecombined, washed with saturated sodium hydrogen carbonate solution,water, brine and then dried (MgSO₄) and evaporated. Purification byflash chromatography on silica gel (hexane, 1:2 CH₂Cl₂/hexanes and then2:1 CH₂Cl₂/hexanes as elutants) provided 147A as a colorless oil, 48 g(80%).

[0355] To a stirred solution of 147A (47.8 g, 159 mmol), imidazole (26g, 382 mmol) and triphenyl phosphine (45.9 g, 175 mmol) in THF (220 mL)at 5° C. under argon was added a solution of iodine (44.4 g, 175 mmol)in THF (200 mL) at such a rate as to keep the reaction temperature below15° C. After complete addition, the reaction mixture was warmed to roomtemperature and stirred overnight. The reaction was quenched with 5%sodium bisulfite solution and extracted twice with Et₂O (150 mLportions). The extracts were combined, washed with water and brine anddried (MgSO₄). Evaporation, followed by trituration of the residue inhexanes, filtration and re-evaporation of the filtrate gave 147B as awhite solid, 57.5 g (88%), mp 43-44° C.

[0356] To a stirred solution diethyl malonate (32 mL, 210 mmol) in dryDMF (200 mL) at 0C under argon was added sodium hydride (60% mineral oildispersion, 5.6 g, 140 mmol) in portions, maintaining the solutiontemperature at or below 10° C. When addition was complete, the reactionwas warmed to room temperature. After stirring an additional 1 h, asolution of 147B (57.4 g, 140 mmol) in DMF (200 mL) was added at roomtemperature over 15 min. After 16 h, the solution was diluted with water(1 L) and extracted twice with Et₂O (300 mL portions). The organicextracts were combined, washed with saturated sodium bicarbonatesolution, water and brine, dried (MgSO₄) and evaporated. Purification byflash chromatography on silica gel (hexane/CH₂Cl₂ step gradient)provided 147C as a white solid, 49.5 g (80% yield). LC/MS gave thecorrect molecular ion [(M+H)⁺=443] for the desired compound.

[0357] By the method of 59B, but using 147C product (17.50 g, 39.5mmol), 147D was prepared as a white solid, 15.77 g, (93% yield). LC/MSgave the correct molecular ion [(M+H)⁺=415] for the desired compound.

[0358] To a stirred mixture of 147D (46.34 g, 112 mmol) and2,4-dichlorobenzylamine (15.3 mL, 117 mmol) in CH₂Cl₂ (300 mL) at 5° C.under argon was added N-ethyl-N-(N′,N-dimethylaminoethyl) carbodiimidehydrochloride (EDAC, 22.5 g, 117 mmol) over 20 min. After 30 min, thereaction mixture was warmed to room temperature and stirred for 60 h.The resulting slurry was diluted with water (500 mL) and extracted threetimes with CH₂Cl₂ (200 mL portions). The combined organic extracts werewashed with 10% citric acid solution (400 mL), saturated sodiumbicarbonate solution (400 mL), water and brine and then filtered througha Celite pad. The filtrate was dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (5:1 hexanes/EtOAc)gave 147E as a white solid, 43.5 g, (68% yield) mp 78-80° C. LC/MS gavethe correct molecular ion [(M+H)⁺=572] for the desired compound.

[0359] To a stirred solution of 147E (43.5 g, 76 mmol) in methanol (1500mL) at 0° C. under argon was added ammonia gas until a saturatedsolution was obtained. The reaction mixture was allowed to warm to roomtemperature and stirred under an ammonia atmosphere for 16 h. Thereaction mixture was again cooled to 0° C., re-saturated with ammoniagas, warmed to room temperature and stirred an additional 20 h. Cooling,resaturation and stirring at room temperature was repeated once more.The resulting slurry was evaporated to give 147F as a white solid, 40.0g (97% yield) mp 146-147° C. LC/MS gave the correct molecular ion[(M+H)⁺=542] for the desired compound.

[0360] To a solution 147F (14.0 g, 25.8 mmol) in THF (100 mL) at roomtemperature under argon was added a solution of borane-THF complex (1Min THF, 200 mL, 0.2 mol) dropwise, and the solution was then refluxed.After 18 h, the solution was cooled to 5° C. and quenched by dropwiseaddition of sodium hydroxide solution (1M, 220 mL, 0.22 mol) and thenstirred overnight. The resulting mixture was diluted with water (200 mL)and extracted twice with Et₂O (200 mL portions). The combined extractswere washed with water and brine, dried (Na₂SO₄) and evaporated to give147G as a colorless oil, 13.0 g, (˜100% yield). The material was usedwithout purification for the preparation of 147H.

[0361] To a stirred solution of 147G (23.72 g, 46.0 mmol) andtriethylamine (70 mL, 51 mmol) in CH₃CN (230 mL) at 5° C. under nitrogenwas added a solution of carbonyl diimidazole (CDI, 3.73 g, 23 mmol) inCH₃CN (230 mL) over 30 min. After 1 h, solid CDI (1.24 g, 7.8 mmol) wasadded and, at 1 h intervals, additional CDI was added (1.24 g, 1.24 gand 1.24 g). After the last addition, the reaction mixture was warmed toroom temperature and stirred for 16 h. After evaporation, the residuewas partitioned between 5% potassium hydrogen sulfate solution and EtOAc(500 mL). The organic extract was dried (MgSO₄) and evaporated.Purification by flash chromatography on silica gel (EtOAc) gave 147H asa colorless glass, 14.9 g, (60% yield). LC/MS gave the correct molecularion [(M+H)⁺=541] for the desired compound.

[0362] To a stirred solution of 147H (5.36 g, 9.90 mmol) in THF (40 mL)at room temperature under argon was added a solution oftetrabutylammonium fluoride (1M in THF, 12 mL, 12 mmol). After 2 h, thereaction mixture was evaporated and then partitioned between water andEtOAc. The resulting white solids were collected and dried in vacuo togive 147I, 2.70 g, (90% yield) mp 152-153° C. LC/MS gave the correctmolecular ion [(M+H)⁺=303] for the desired compound.

[0363] To a stirred suspension of 147I (5.0 g, 16.5 mmol) in acetone(120 mL) at room temperature under argon was added a saturated sodiumbicarbonate solution (44 mL). The mixture was cooled to 0° C. andtreated sequentially with potassium bromide (196 mg, 1.65 mmol) andTEMPO (2.71 g, 17.3 mmol). To the resulting mixture was added a solutionof sodium hypochlorite (˜4%, 40.5 mL) over 15 min. After 1 h, additionalsodium hypochlorite solution (15.6 mL) was added and the reactionstirred for 1 h. The reaction mixture was quenched with saturated sodiumbicarbonate solution (100 mL) and extrated three times with ether (100mL portions). The aqueous phase was separated and brought to pH 2 withsolid citric acid. The resulting white solids were collected, washedwith water and dried in vacuo to give 147J, 4.40 g, (84% yield) mp206-207° C. LC/MS gave the correct molecular ion [(M+H)⁺=317] for thedesired compound.

[0364] A stirred suspension of 147J (4.65 g, 14.7 mmol) in methanol (150mL) at 0° C. was saturated with hydrogen chloride gas. The resultingsolution was warmed to room temperature, stirred for 2 h and thenevaporated. The residue was dissolved in CH₂Cl₂ (150 mL), washed withsaturated sodium bicarbonate solution (100 mL), water and brine. Theorganic extract was dried (Na₂SO₄) and evaporated to give 147K as alight yellow glass, 4.61 g, (95% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=331] for the desired compound.

EXAMPLES 148-185

[0365] The title compounds were prepared as part of a solution phaselibrary run using the following procedure.

[0366] To a solution of 147K (33.1 mg, 0.1 mmol) and tetrabutylammoniumiodide (37 mg, 0.1 mmol) in THF (0.4 mL) under argon at room temperaturewas added a solution of potassium hexamethyl disilazide (0.5M intoluene, 210 μL, 0.105 mmol) and the mixture was shaken for 50 min. Tothis mixture was added a solution of R—X (0.16 mmol) in THF (0.4 mL).The reaction mixtures were shaken in a nitrogen atmosphere at roomtemperature for 18 h. The reactions were then each treated with asolution of potassium trimethylsilyloxide (51 mg, 0.33 mmol) in THF (0.5mL) for 5 h at 40° C. Each reaction was then filtered and the filtratesevaporated. Each reaction was purified by reverse-phase HPLC(water/CH₃CN-0.2% TFA gradient). Mass spectrometric and HPLC data werecollected for all compounds.

[0367] Following the above procedure, the following compounds of theinvention were prepared: (M + H) positive Ex. X—R Structure Name ions148

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-hexyl-2-oxo-5-pyrimidineacetic acid 401 149

1-[(2,4-Dichloro- phenyl)methyl]-3-(3- fluoropropyl)hexa- hydro-2-oxo-5-pyrimidineacetic acid 377 150

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(3,5,5-trimethylhexyl)-5- pyrimidineacetic acid 443 151

1-[(2,4-Dichloro- phenyl)methyl]-3-(3,7- dimethyl-2,6- octadienyl)hexa-hydro-2-oxo-5- pyrimidineacetic acid 453 152

1-[(2,4-Dichloro- phenyl)methyl]-3-(2- ethoxyethyl)hexahydro-2-oxo-5-pyrimidine- acetic acid 389 153

1-[(2,4-Dichloro- phenyl)methyl]hexahy- dro-3-(1-methyl- butyl)-2-oxo-5-pyrimidineacetic acid 387 154

1-(Cyclopropyl- methyl)-3-[(2,4- dichlorophenyl)- methyl]hexahydro-2-oxo-5-pyrimidine- acetic acid 371 155

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-[3-(1H-pyrrol-1-yl)-propyl]-5- pyrimidine-acetic acid 424 156

1-[(5-Chloro-2- thienyl)methyl]-3- [(2,4-dichloro- phenyl)methyl]hexa-hydro-2-oxo-5- pyrimidineacetic acid 448 157

1-[(2,4-Dichloro- phenyl)methyl]-3-[[5- (1,1-dimethylethyl)-1,2,4-oxadiazol-3- yl]methyl]hexahydro- 2-oxo-5-pyrimidine- acetic acid455 158

1-[(2,4-Dichloro- phenyl)methyl]-3- [(3,5-dimethyl-4-isoxazolyl)methyl - hexahydro-2-oxo-5- pyrimdineacetic acid 426 159

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[[5-(4- methoxyphenyl)-1,2,4-oxadiazol-3- yl]methyl]-2-oxo-5- pyrimidineacetic acid 505 160

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-[[5-(3-thienyl)-1,2,4-oxadi- azol-3-yl]methyl]-5- pyrimidineacetic acid 481 161

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(3-phenoxypropyl)-5- pyrimidineacetic acid 451 162

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[3-methoxy-3-(4-methylphenyl)- propyl]-2-oxo-5- pyrimidineacetic acid 479 163

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[3-[methyl-(phenylmethyl)amino]propyl]-2-oxo-5- pyrimidineacetic acid 478 164

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(5- phenylpentyl)-5-pyrimidineacetic acid 463 165

1-[4-Cyano-4-(2- methylphenyl)butyl]-3- [(2,4-dichloro-phenyl)methyl]hexa- hydro-2-oxo-5- pyrimidineacetic acid 488 166

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-[[4-(phenylmethoxy)- phenyl]methyl]-5- pyrimidineacetic acid 513 167

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[3-[(3-methylphenyl)thio]- propyl]-2-oxo-5- pyrimidineacetic acid 481 168

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(3-phenyl-2-propenyl)-5- pyrimidineacetic acid 433 169

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[[4-(methyl-sulfonyl)phenyl]- methyl]-2-oxo-5- pyrimidineacetic acid 485 170

1-[(3-Cyanophenyl)- methyl]-3-[(2,4- dichlorophenyl)me-thyl]hexahydro-2-oxo- 5-pyrimidine-acetic acid 432 171

1-[(2,4-Dichloro- phenyl)methyl]hexahy- dro-3-[(2-methoxy-5-nitrophenyl)-methyl]- 2-oxo-5- pyrimidineacetic acid 482 172

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-(1- naphthalenylmethyl)-2-oxo-5-pyrimi- dineacetic acid 457 173

1-(1,3-Benzodioxol-5- ylmethyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5- pyrimidineacetic acid 451 174

1-[(2,4-Dichloro- phenyl)methyl]-3- [(2,4-difluoro- phenyl)methyl]hexa-hydro-2-oxo-5- pyrimidineacetic acid 443 175

1-(2-Cyclohexyl- ethyl)-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5- pyrimidineacetic acid 427 176

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[[4-(methyl-thio)phenyl]methyl]-2- oxo-5-pyrimidine- acetic acid 453 177

1-(4-Cyanobutyl)-3- [(2,4-dichloro- phenyl)methyl]hexa- hydro-2-oxo-5-pyrimidineacetic acid 398 178

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-[3-(phenylmethoxy)pro- pyl]-5-pyrimidine- acetic acid 465 179

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[2-(2-methoxyethoxy)ethyl]- 2-oxo-5-pyrimidine- acetic acid 419 180

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(4,4,4-trifluorobutyl)-5- pyrimidineacetic acid 427 181

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-(3-methyl-2-butenyl)-2-oxo-5- pyrimidineacetic acid 385 182

1-[(2,4-Dichloro- phenyl)methyl]-3-(2- ethylhexyl)hexahydro-2-oxo-5-pyrimidine- acetic acid 429 183

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(4- pentenyl)-5-pyrimidineacetic acid 385 184

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-2-oxo-3-(3- phenylpropyl)-5-pyrimidineacetic acid 435 185

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-(2-iodo-phenyl)methyl]-2-oxo- 5-pyrimidine-acetic acid 533

EXAMPLE 186 Methyl1-[(2-Carboxyphenyl)methyl]-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetate

[0368]

[0369] A mixture of phthalide (5.36 g, 40 mmol) and triphenylphosphoniumdibromide (6.90 g, 40.0 mmol) was heated to 170° C. under argon for 3 hand then to 180° C. for 1 h. After cooling to room temperature, thereaction mixture was dissolved in CH₂Cl₂ (40 mL) to give a dark brownsolution. This was added to a solution of diphenylmethanol (7.37 g, 40mmol) and N-ethyl-N,N-diisopropylamine (14 mL, 80 mmol) in CH₂Cl₂ (40mL) at 0° C. over 30 min. After an additional 30 min, the reaction waswarmed to room temperature and stirred overnight and then evaporated.The residual material was dissolved in Et₂O (400 mL) and the remainingsolids filtered. The filtrate was washed with 10% citric acid solution(100 mL) and half-saturated sodium bicarbonate solution (100 mL). Theorganic extract was dried (Na₂SO₄) and evaporated. Purification by flashchromatography on silica gel (1:2 CH₂Cl₂/hexanes as elutant) provided186A as a colorless oil, 7.18 g (47%).

[0370] To a stirred solution of 147K (1.98 g, 6.00 mmol) in THF (40 mL)at room temperature under argon was added potassium hexamethyldisilazidesolution (0.5M in toluene, 12.6 mL, 6.3 mmol). After 5 min, a solutionof 186A (3.43 g, 9.00 mmol) in THF (10 mL) was added in one portion,followed by tetrabutylammonium iodide (2.21 g, 6.0 mmol). After 16 h,the reaction mixture was partitioned between saturated sodiumbicarbonate solution and Et₂O. The organic phase was dried (Na₂SO₄) andevaporated. Purification by flash chromatography (1:2 EtOAC/hexanes aselutant). Evaporation gave 186B as a white solid, 2.20 g (58%).

[0371] To a stirred solution of 186B (2.68 g, 4.24 mmol) and anisole(1.85 mL, 17.0 mmol) in CH₂Cl₂ (20 mL) at 0° C. under argon was addedtrifluoroacetic acid (10 mL). After 2 h, the reaction mixture was pouredinto saturated sodium bicarbonate solution (200 mL) and then solidsodium bicarbonate was added with stirring to bring the mixture to pH 8.The mixture was extracted with hexane and then Et₂O. The aqueous phasewas cooled to 5° C. and acidified to pH 3 with 10% phosphoric acidsolution. The resulting mixture was extracted twice with CH₂Cl₂. TheCH₂Cl₂ extracts were combined, dried (MgSO₄) and evaporated to give 186Cas a white amorphous solid, 1.76 g (89% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=465] for the desired compound.

EXAMPLE 187 Methyl1-[(2-Chlorocarbonylphenyl)methyl]-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineacetate

[0372]

[0373] To a stirred solution of 186C (1.21 g, 2.6 mmol) in CH₂Cl₂ (20mL) at room temperature under argon was added oxalyl chloride solution(2M in CH₂Cl₂, 6.5 mL, 13 mmol) and DMF (2 drops). After 3 h, thereaction mixture was evaporated, dissolved in toluene and re-evaporated.The yellow oil was dissolved in CH₂Cl₂ (26.0 mL) to provide 187 as alight yellow solution, 0.1M.

EXAMPLES 188-235

[0374] The title compounds were prepared as part of a solution phaselibrary run using the following procedure.

[0375] To RR′NH or RR′NH.HCl or RR′NH.2HCl (0.075 mmol) pre-weighed in a2 dram vial was added a solution of triethylamine (0.375M in CH₂Cl₂, 0.4mL, 0.15 mmol). For amine hydrochloride salts, additional triethylaminewas added (21 μL, 0.15 mmol for monohydrochlorides; 42 μL fordihydrochlorides). To this solution was added Example 187 solution (0.5mL, 0.05 mmol) and the reaction vessels were sealed and agitated for 24h. The reaction mixtures were evaporated and treated with a solution ofpotassium trimethylsilyloxide (38 mg, 0.3 mmol) in THF (0.5 mL) at roomtemperature for 18 h. The reaction mixtures were diluted with methanol(1 mL), filtered and the filtrates evaporated. Each reaction waspurified by reverse-phase HPLC (water/CH₃CN-0.2% TFA gradient).

[0376] Mass spectrometric and HPLC data were collected for allcompounds. Following the above procedure, the following compounds of theinvention were prepared: (M + H) positive Ex. Structure Name ions 188

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(4-phenoxyphenyl)- amino]carbonyl]phenyl]methyl]-5-pyrimidineacetic acid 618 189

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(3-phenoxyphenyl)- amino]carbonyl]phenyl]methyl]-5-pyrimidineacetic acid 618 190

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(2-phenoxyphenyl)- amino]carbonyl]phenyl]methyl]-5-pyrimidineacetic acid 618 191

1-[[2-[[(3-Chlorophenyl)- amino]carbonyl]phenyl]m ethyl]-3-[(2,4-dichlorophenyl)- methyl]hexahydro-2-oxo- 5-pyrimidineacetic acid 560 192

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[(phenylamino)-carbonyl]phenyl]methyl]- 5-pyrimidineacetic acid 526 193

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[(2-methoxyphenyl)-amino]carbonyl]phenyl]- methyl]-2-oxo-5-pyrimi- dineacetic acid 556 194

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[[4-(2-hydroxyethyl)phenyl]- amino]carbonyl]-phenyl]methyl]-2-oxo-5-pyrimi-dineacetic acid 570 195

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[[[3-(phenyl-methoxy)-phenyl]amino]- carbonyl]phenyl]methyl]5-pyrimidineacetic acid632 196

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[[[4-(phenyl-methoxy)-phenyl]amino]- carbonyl]phenyl]methyl]- 5-pyrimidineacetic acid632 197

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(4-nitrophenyl)-ethyl]amino]carbonyl]phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 599198

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[(3-hydroxypropyl)-(phenylmethyl)amino]- carbonyl]phenyl]methyl]- 2-oxo-5-pyrimidineaceticacid 598 199

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(3-hydroxyphenyl)-ethyl]amino]carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 570200

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[(propylamino)-carbonyl]phenyl]methyl]- 5-pyrimidineacetic acid 492 201

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[(hexyl-amino)- carbonyl]phenyl]-methyl]hexahydro-2-oxo-5- pyrimidineacetic acid 534 202

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[[[[(1S,2R,5S)-6,6-dimethylbicyclo-[3.1.1]hept- 2-yl]methyl]-amino]-carbonyl]-phenyl]-methyl]hexa-hydro-2- oxo-5-pyrimidineacetic acid 586 203

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(2-phenylethyl)-amino]- carbonyl]phenyl]methyl]-5-pyrimidineacetic acid 554 204

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[methyl(2-phenylethyl)- amino]carbonyl]phenyl]- methyl]-2-oxo-5-pyrimidineacetic acid 568 205

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[[2-(3-ethoxy-4-methoxy- phenyl)-ethyl]amino]- carbonyl]phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 628 206

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(3-phenylpropyl)- amino]-carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 568 207

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[[2-(2-thienyl)ethyl]- amino]-carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 560 208

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(4-phenylbutyl)- amino]-carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 582 209

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[4-(phenylmethyl)-1- piperi-dinyl]carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 608 210

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[[[3-(2-oxo-1-pyrrolidinyl)-propyl]- amino]carbonyl]phenyl]- methyl]-5-pyrimidine-acetic acid 575 211

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(2,2,2-trifluoro- ethyl)-amino]carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 532 212

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[(dimethyl-amino)-carbonyl]phenyl]- methyl]hexa-hydro-2-oxo- 5-pyrimidineaceticacid 478 213

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[(3,5- dimethyl-1-piperidinyl)-carbonyl]phenyl]methyl]- hexahydro-2-oxo-5- pyrimidineacetic acid 546214

1-[(2,4-Dichloro- phenyl)methyl]hexa- hydro-3-[[2-[[(3-methoxy-propyl)amino]carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid522 215

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[[(2-ethyl-hexyl)amino]carbonyl]phe nyl]-methyl]hexahydro-2- oxo-5-pyrimidineaceticacid 562 216

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[(2-phenoxyethyl)- amino]carbonyl]phenyl]- methyl]-5-pyrimidine-acetic acid 570 217

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[[[4- (dimethyl-amino)phenyl]-amino]carbonyl]phenyl]- methyl]hexahydro-2-oxo- 5-pyrimidineacetic acid569 218

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[4-(2-hydroxyethyl)-1-piperazinyl]-carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid563 219

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(1-methyl-2-pyrrolidinyl)-ethyl]amino]- carbonyl]phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 561 220

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(4-morpholinyl)-ethyl]amino]carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 563221

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo- 3-[[2-[(4-phenyl-1-piperazinyl)car-bonyl]- phenyl]methyl]-5- pyrimidineacetic acid 595 222

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[4-(phenylmethyl)-1- piperazinyl]carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 609 223

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[[2-(1H-indol-3-yl)ethyl]- methyl-amino]carbonyl]-phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 607 224

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[methyl[2-(2-pyridinyl)- ethyl]-amino]carbonyl]-phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 569 225

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(1H-imidazol-4-yl)ethyl]amino]-carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid544 226

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[[2-(1H-indol-3-yl)ethyl]- amino]-carbonyl]- phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 593 227

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[3-(1H-imidazol-1-yl)propyl]-amino]- carbonyl]phenyl]methyl]- 2-oxo-5-pyrimidineaceticacid 558 228

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[[2-(2-pyridinyl)- ethyl]-amino]carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 555 229

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[[2-(1H-pyrrol-1- yl)ethyl]-amino]carbo- nyl]phenyl]methyl]-5-pyrimidineacetic acid 547 230

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[[[3- (dimethyl-amino)propyl]-amino]carbonyl]-phenyl]methyl]hexahydro-2-oxo- 5-pyrimidineacetic acid535 231

1-[(2,4-Dichlorophenyl)- methyl]-3-[[2-[[[2- (dimethyl-amino)ethyl]-(phenylmethyl)-amino]- carbonyl]phenyl]methyl]- hexahydro-2-oxo-5-pyrimidine-acetic acid 611 232

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2-[[4-(2-methoxyphenyl)-1- pipera-zinyl]carbonyl]- phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 625 233

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-2-oxo-3-[[2-[[[2-(phenylamino)- ethyl]-amino]carbonyl]- phenyl]methyl]-5-pyrimidineacetic acid 569 234

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-[[2- [[[2-(1-methyl-1H-imi-dazol-5-yl)ethyl]- amino]carbonyl]- phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 558 235

1-[(2,4-Dichlorophenyl)- methyl]hexahydro-3-(2- iodophenyl)methyl]-2-oxo-5-pyrimidineacetic acid 533

EXAMPLE 2361-[(2-Carboxyphenyl)methyl]-3-[(2,4-dichlorophenyl)methyl]hexahydro-2-oxo-5-pyrimidineaceticacid

[0377]

[0378] A mixture of phthalide (3.35 g, 25 mmol) and triphenylphosphoniumdibromide (10.6 g, 25.1 mmol) was heated to 170° C. under argon for 3 hand then to 180° C. for 1 h. After cooling to room temperature, thereaction mixture was dissolved in CH₂Cl₂ (30 mL). This was added tomethanol (20 mL) at 0° C. over 30 min. After an additional 1 h, thereaction was warmed to room temperature and then evaporated. Theresidual material was evaporated onto silica gel (21 g). Purification byflash chromatography on silica gel (1:3 CH₂Cl₂/hexanes as elutant)provided 236A as a colorless oil, 3.90 g (68%).

[0379] To a stirred solution of 147K (50 mg, 0.15 mmol) in THF (0.5 mL)at room temperature under argon was added potassium hexamethyidisilazidesolution (0.5M in toluene, 310 μL, 0.155 mmol). After 5 min, 235A (38.0mg, 0.165 mmol) was added in one portion, followed by tetrabutylammoniumiodide (55.4 mg, 0.15 mmol). After 1 h, the reaction mixture waspartitioned between saturated sodium bicarbonate solution and Et₂O. Theorganic phase was dried (Na₂SO₄) and evaporated. Purification by flashchromatography (1:1 EtOAC/hexanes as elutant). Evaporation gave 236B, 42mg (58%).

[0380] To a stirred solution of 236B (42 mg, 0.088 mmol) in THF (1 mL)at room temperature under argon was added sodium hydroxide (1M, 1 mL, 1mmol). After 17 h, the reaction mixture was extracted twice with Et₂O.The aqueous phase was cooled to 0° C. and acidified to pH 3 with 1Mhydrochloric acid. The resulting precipitate was collected, washed withwater and dried in vacuo to give 236C as a white solid, 40 mg (100%yield), mp 212-213° C. LC/MS gave the correct molecular ion [(M+H)⁺=451]for the desired compound.

EXAMPLE 237 t-Butyl1-(4-Bromophenyl)-hexahydro-2-oxo-5-pyrimidineacetate

[0381]

[0382] A.

[0383] To a stirred solution of chromium trioxide (6.05 g, 60.5 mmol) inCH₂Cl₂ (40 mL) and DMF (10 mL) at room temperature was added pyridine(9.8 mL, 121 mmol). The mixture was stirred for 15 min and then asolution of 8E (6.1 g, 15 mmol) in CH₂Cl₂ (20 mL) and DMF (5 mL) wasadded, followed immediately by acetic anhydride (11.6 mL, 121 mmol) andt-butanol (28 mL, 302 mmol). After 16 h, the reaction mixture wasdiluted with ethanol (10 mL) and stirred for 15 min. Ether (200 mL) wasthen added and the slurry was filtered through Celite. The filtrate waswashed with water and brine, dried (Na₂SO₄) and evaporated. Purificationby flash chromatography on silica gel (2:1 hexanes/EtOAc as elutant)provided 237A as a colorless glass, 3.80 g (53%). LC/MS gave the correctmolecular ion [(M+H)⁺=475] for the desired compound.

[0384] To a stirred solution of ceric ammonium nitrate (13.0 g, 24 mmol)in water (40 mL) at −10° C. was added a solution of 237A (3.80 g, 7.99mmol) in CH₃CN (60 mL) over 30 min. After an additional 15 min, thereaction mixture was quenched with 10% sodium acetate solution to pH 7.The mixture was extracted three times with EtOAc (150 mL portions) andthe combined organic extracts were washed with 10% sodium sulfitesolution (buffered to pH 7 with sodium bisulfite), water and brine. Theorganic phase was dried (Na₂SO₄) and evaporated. Purification by flashchromatography on silica gel (EtOAc as elutant) gave 237B as a colorlessoil, 1.18 g (40% yield). LC/MS gave the correct molecular ion[(M+H)⁺=369] for the desired compound.

[0385] To a stirred solution of 237B (1.11 g, 3.00 mmol) in THF (20 mL)at room temperature under nitrogen was added potassiumhexamethyldisilazide solution ( 0.5M in toluene, 6.3 mL, 3.2 mmol).After 5 min, a solution of 236A (756 mg, 3.3 mmol) in THF (10 mL) wasadded, followed by tetrabutylammonium iodide (1.11 g, 3.0 mmol). After 3h, the reaction mixture was quenched with saturated ammonium chloridesolution and extracted three times with Et₂O (100 mL portions). Thecombined organic extracts were washed with water and brine. The organicphase was dried (Na₂SO₄) and evaporated. Purification by flashchromatography on silica gel (1:2 EtOAc/hexanes as elutant) gave 237C asa colorless amorphous solid, 1.41 g (91% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=517] for the desired compound.

[0386] To a stirred solution of 237C (1.40 g, 2.71 mmol) in THF (5 mL)at room temperature under nitrogen was added potassiumtrimethylsilyloxide (0.381 g, 3.0 mmol). The reaction was monitored tominimize loss of the t-butyl ester. After 3 h, the reaction mixture wasevaporated, diluted with water (5 mL), cooled to 5° C. and treated with0.3N potassium hydrogen sulfate solution to pH 4. The reaction mixturewas then extracted three times with CH₂Cl₂ (40 mL portions. The combinedorganic extracts were washed with water and brine. The organic phase wasdried (Na₂SO₄) and evaporated. Purification by flash chromatography onsilica gel (190:10:1 CH₂Cl₂/CH₃OH/HOAc as elutant) gave 237D as acolorless amorphous solid, 620 mg (45% yield). LC/MS gave the correctmolecular ion [(M+H)⁺=503] for the desired compound.

EXAMPLES 238-257

[0387] The title compounds were prepared as part of a solution phaselibrary run using the following procedure.

[0388] To 237D (35 mg, 0.07 mol), RR′NH (0.139 mmol), and HOAt (19 mg,0.14 mol) in CH₂Cl₂ (1 mL) at room temperature was added EDAC (27 mg,0.14 mmol) and the reaction vessels were sealed and agitated for 24 h.The reaction mixtures were evaporated and treated with a solution ofpotassium trimethylsilyloxide (38 mg, 0.3 mmol) in THF (0.5 mL) at roomtemperature for 18 h. The reaction mixtures were diluted with methanol(1 mL), filtered and the filtrates evaporated. Each reaction waspurified by reverse-phase HPLC (water/CH₃OH—0.2% TFA gradient).

[0389] Mass spectrometric and HPLC data were collected for allcompounds. Following the above procedure, the following compounds of theinvention were prepared: (M + H) positive Ex. Structure Name ion 238

1-(4-Bromophenyl)-3-[[2- [[[[(1a,2b,5a)-6,6-dimethyl-bicyclo[3.1.1]hept-2- yl]methyl]amino]carbonyl]-phenyl]methyl]hexahydro-2- oxo-5-pyrimidineacetic acid 582 239

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2- [[[3-(2-oxo-1-pyrroli-dinyl)propyl]amino]car- bonyl]phenyl]methyl]-5- pyrimidineacetic acid571 240

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[3-(4-morpholinyl)propyl]amino]carbonyl]phenyl]methyl]-2-oxo-5-pyrimidineacetic acid 573 241

1-(4-Bromophenyl)- hexahydro-3-[[2- [[methyl[2-(2-pyridinyl)-ethyl]amino]carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid 565242

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[2-(1H- imidazol-2-yl)ethyl]amino]-carbonyl]phenyl]methyl]-2- oxo-5-pyrimidineacetic acid 540 243

1-(4-Bromophenyl)-3-[[2- [(hexylamino)carbonyl]phenyl]methyl]hexahydro-2- oxo-5-pyrimidineacetic acid 530 244

1-(4-Bromophenyl)-3-[[2- [[(2,2,3,3,4,4,4-hepta- fluorobutyl)amino]car-bonyl]phenyl]methyl]hexa- hydro-2-oxo-5-pyrimi- dineacetic acid 628 245

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[3-(1H- imidazol-1-yl)propyl]-amino]carbonyl]phenyl]- methyl]-2-oxo-5- pyrimidineacetic acid 554 246

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2- [[[2-(2-pyridinyl)ethyl]-amino]carbonyl]phenyl]- methyl]-5-pyrimidineacetic acid 551 247

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[2-(1H- indol-3-yl)ethyl]amino]-carbonyl]phenyl]methyl]-2- oxo-5-pyrimidineacetic acid 589 248

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2-[[4- (phenylmethyl)-1-pipera-zinyl]carbonyl]-phenyl]- methyl]-5-pyrimidineacetic acid 605 249

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2-[[4- (phenylmethyl)-1-piperi-dinyl]carbonyl]-phenyl]- methyl]-5-pyrimidine- acetic acid 604 250

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[2-(1H- indol-3-yl)ethyl]methyl-amino]carbonyl]phenyl]- methyl]-2-oxo-5-pyrimi- dineacetic acid 603 251

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[2-(1- methyl-1H-imidazol-5-yl)ethyl]amino]-carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid554 252

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2- [[[2-(1-piperidinyl)-ethyl]-amino]carbonyl]phenyl]- methyl]-5-pyrimidineacetic acid 557 253

1-(4-Bromophenyl)- hexahydro-2-oxo-3-[[2- [[[2-(1-pyrrolidinyl)-ethyl]amino]carbonyl]- phenyl]methyl]-5- pyrimidineacetic acid 543 254

1-(4-Bromophenyl)- hexahydro-3-[[2-[[(3- hydroxypropyl)-(phenyl-methyl)amino]carbonyl]- phenyl]methyl]-2-oxo-5- pyrimidineacetic acid594 255

1-(4-Bromophenyl)- hexahydro-3-[[2- [[methyl(2-phenylethyl)-amino]carbonyl]phenyl]- methyl]-2-oxo-5- pyrimidineacetic acid 564 256

1-(4-Bromophenyl)- hexahydro-3-[[2-[[[(2S)-2- hydroxy-2-phenylethyl]-amino]carbonyl]-phenyl]- methyl]-2-oxo-5- pyrimidineacetic acid 566 257

1-(4-Bromophenyl)-3-[[2-[(dimethylamino)carbonyl]phenyl]methyl]hexahydro-2-oxo-5-pyrimidineacetic acid 474

EXAMPLE 2581-[(2,4-Dichlorophenyl)methyl]hexahydro-2-oxo-3-(phenylmethyl)-5-pyrimidineaceticacid

[0390]

[0391] By the method of examples 148-185, using 147K and benzyl bromideas the alkylating agent, the title compound was prepared. LC/MS gave thecorrect molecular ion [(M+H)⁺=407].

We claim:
 1. A compound of formula I

enantiomers, diastereomers, pharmaceutically acceptable salts andprodrug esters thereof wherein A and B are the same or different and areindependently —J, —(CR³R⁴)_(n)—J, —R⁵(CR³R⁴)_(p)—J,—(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—J, —(CR³R⁴)_(n)(CR⁶R⁷)_(p)—J, —S(O)J where Jis other than hydrogen, —S(O₂)J where J is other than hydrogen, and—NH(CR³R⁴)_(n)—J; J is independently R¹ or R²; R¹ and R² areindependently hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl,substituted heteroaralkyl, cycloheteroalkyl and substitutedcycloheteroalkyl; R³and R⁴ are the same or different and areindependently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, arylcarbonyl, aryl and heteroaryl, halo, hydroxy,alkoxy and aryloxy; or R³ and R⁴ together with the atom to which theyare bonded may form a 3 to 9-membered saturated or unsaturated ring. R⁵is a bond, O, NR⁸, S, SO, SO₂, CO or CONH; R⁶ and R⁷ are the same ordifferent and are independently H, alkyl, cycloalkyl, aryl, hydroxy,amino, halo, alkoxy, aryloxy, alkylthio, arylthio, alkylamino,dialkylamino, arylamino, diarylamino, alkoxycarbonyl, alkylaminocarbonylor alkylcarbonylamino; R⁸ is H, aryl, arylcarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkyl oralkylcarbonyl; R⁹ is H, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl ora prodrug ester thereof; R¹⁰ is H, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl ora prodrug ester thereof; R¹¹ is hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl andsubstituted cycloheteroalkyl; R¹² and R¹³ are the same or different andare independently H, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl or a prodrugester thereof; or R¹² and R¹³ together with the nitrogen atom to whichthey are bonded together form an optionally substituted cycloheteroalkylring; X is selected from —Z, —(CR³R⁴)_(n)—Z, —O—(CR³R⁴)_(p)—Z,—S—(CR³R⁴)_(p)—Z, —NHC(═O)Z, —CH═CHZ, -(cycloalkylene)-Z, or—N(R⁸)(CR³R⁴)_(n)—Z; Y is H, alkyl, aryl, aralkyl, alkoxy, aryloxy,alkylthio, arylthio, hydroxy, —(CR³R⁴)_(n)—CO₂R⁹, —(CR³R⁴)_(n)—CONR¹²R³,—NR³R⁴, aralkoxy, or heteroarylalkyl, provided that Y is other thanhydroxy or NH₂ when X is —O(CR³R⁴)_(p)—Z, —S(CR³R⁴)_(p)—Z, —NHC(═O)Z, or—N(R⁸)(CR³R⁴)_(n)—Z; or X and Y, taken together with the atom to whichthey are joined, provide a group of the formula

Z is CO₂R⁹, SO₃H, PO₃R⁹R¹⁰, CONHOH, CONR¹²R¹³, (CR³R⁴)_(m)OH, ortetrazole of the formula

or its tautomer; n is an integer selected from 0 to 5; m is an integerselected from 1 to 5; and p is an integer selected from 0 to
 4. 2. Thecompound of claim 1 wherein A is —R¹, —(CR³R⁴)_(n)—R¹,—R⁵(CR³R⁴)_(p)—R¹, —(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—R¹,—(CR³R⁴)_(n)(CR⁶R⁷)_(p)—R¹, —S(O)R¹ where R¹ is other than hydrogen,—S(O₂)R¹ where R¹ is other than hydrogen, or —NH(CR³R⁴)_(n)—R¹; R¹ issubstituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkyl or cycloalkyl; B is —R², —(CR³R⁴)_(n)—R²,—R⁵(CR³R⁴)_(p)—R², —(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—R²,—(CR³R⁴)_(n)(CR⁶R⁷)_(p)—R², —S(O)R² where R² is other than hydrogen,—S(O₂)R² where R² is other than hydrogen, or —NH(CR³R⁴)_(n)—R²; R² isaryl, substituted aryl, cycloalkylalkyl, heteroaryl or substitutedheteroaryl; and Z is CO₂R⁹, CONR¹²R¹³, PO₃H₂, CONHOH, or tetrazole. 3.The compound of claim 2 wherein Y is hydrogen, OH, or—(CR³R⁴)_(n)—CO2R⁹, or X and Y taken together with the atom to whichthey are joined provide a group of the formula


4. The compound of claim 3 wherein A is R¹; B is (CR³R⁴)_(n)—R² where nis 1 and R³ and R⁴ are the same or different and are selected fromhydrogen, alkyl and substituted alkyl; X is (CR³R⁴)_(n)—Z where n is 0or 1 and R¹ and R⁴ are the same or different and are selected fromhydrogen, hydroxy, alkyl and substituted alkyl; or X and Y, takentogether with the atom to which they are joined, provide a group of theformula


5. The compound as defined in claim 4 wherein R¹ is (a) alkylsubstituted with one or more groups selected from aryl, aryloxy andalkoxy, or (b) optionally substituted phenyl; B is (CR³R⁴)_(n)—R² wheren is 1 and R³ and R⁴ are each hydrogen; R² is phenyl, napthyl,substituted phenyl or substituted napthyl; X is (CR³R⁴)_(n)—Z where n is0 or 1 and R³ and R⁴ are hydrogen; and Z is CO₂H, CONR¹²R¹³ ortetrazole.
 6. The compound as defined in claim 5 wherein R¹ is(aryl)alkyl, (aryloxy)alkyl, or phenyl independently substituted withone or more halogen, alkoxy, or aryloxy; R² is phenyl or napthylindependently substituted with one or more halogen, alkyl, substitutedalkyl, alkoxy; arylalkoxy, aryloxy or cyano; Y is hydrogen or —CH₂CO₂H;X is (CR³R⁴)_(n)—Z where n is 1 and R³ and R⁴ are hydrogen; and Z isCO₂H or CONR¹²R¹³.
 7. The compound of claim 6 wherein one R¹² and R¹³ ishydrogen and the other is optionally substituted aryl, optionallysubstituted cycloheteroalkyl or optionally substituted cycloalkyl.
 8. Acompound of formula II

enantiomers, diastereomers, and salts thereof wherein A and B are thesame or different and are independently —J, —(CR³R⁴)_(n)—J,—R⁵(CR³R⁴)_(p)—J, —(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—J,—(CR³R⁴)_(n)(CR⁶R⁷)_(p)—J, —S(O)J where J is other than hydrogen,—S(O₂)J where J is other than hydrogen, and —NH(CR³R⁴)_(n)—J; J isindependently R¹ or R²; R¹ and R² are independently hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aralkyl,substituted aralkyl, heteroaralkyl, substituted heteroaralkyl,cycloheteroalkyl and substituted cycloheteroalkyl; R³ and R⁴ are thesame or different and are independently H, alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,alkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, aryl andheteroaryl, halo, hydroxy, alkoxy and aryloxy; or R³ and R⁴ togetherwith the atom to which they are bonded may form a 3 to 9-memberedsaturated or unsaturated ring; R⁵ is a bond, O, NR⁸, S, SO, SO₂, CO orCONH; R⁶ and R⁷ are the same or different and are independently H,alkyl, cycloalkyl, aryl, hydroxy, amino, halo, alkoxy, aryloxy,alkylthio, arylthio, alkylamino, dialkylamino, arylamino, diarylamino,alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino; R⁸ is H, aryl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aryloxycarbonyl, alkyl or alkylcarbonyl; X* is —W, —(CR³R⁴)_(n)—W,—O(CR³R⁴)_(n)—W, —S(CR³R⁴)_(n)—W, —NHC(═O)W, —CH═CHW,-(cycloalkylene)-W, or —N(R⁸)(CR³R⁴)_(n)—W; Y is H, alkyl, alkenyl,aryl, aralkyl, heteroarylalkyl, alkoxy, aryloxy, aralkoxy, alkylthio,arylthio, hydroxy, or NR³R⁴ provided that Y is other than hydroxy or NH₂when X is —O(CR³R⁴)_(p)—W, —S(CR³R⁴)_(p)—W, —NHC(═O)W, or—N(R⁸)(CR³R⁴)_(n)—W; W is cyano, halogen, hydroxy, alkenyl, C(O)Cl, orC(O)H. or X* and Y, taken together with the atom to which they arejoined, provide a group of the formula

n is an integer selected from 0 to 5; m is an integer selected from 1 to5; and p is an integer selected from 0 to
 4. 9. The compound as definedin claim 8 wherein A is —R¹, —(CR³R⁴)_(n)—R¹, —R⁵(CR³R⁴)_(p)—R¹,—(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—R¹, —(CR³R⁴)_(n)(CR⁶R⁷)_(p)—R¹, —S(O)R¹ whereR¹ is other than hydrogen, —S(O₂)R¹ where R¹ is other than hydrogen, or—NH(CR³R⁴)_(n)—R¹; R¹ is substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkyl or cycloalkyl; B is —R²,—(CR³R⁴)_(n)—R², —R⁵(CR³R⁴)_(p)—R², —(CR³R⁴)_(m)R⁵(CR⁶R⁷)_(p)—R²,—(CR³R⁴)_(n)(CR⁶R⁷)_(p)—R², —S(O)R² where R² is other than hydrogen,—S(O₂)R² where R² is other than hydrogen, or —NH(CR³R⁴)_(n)—R²; R² isaryl, substituted aryl, cycloalkylalkyl, heteroaryl or substitutedheteroaryl.
 10. The compound of claim 9 wherein Y is hydrogen, OH oralkenyl, or X* and Y taken together with the atom to which they arejoined provide a group of the formula


11. The compound of claim 10 wherein A is R¹; B is (CR³R⁴)_(n)—R² wheren is 1 and R³ and R⁴ are the same or different and are selected fromhydrogen, alkyl and substituted alkyl; X* is (CR³R⁴)_(n)—W where n is 0or 1 and R³ and R⁴ are the same or different and are selected fromhydrogen, hydroxy, alkyl and substituted alkyl; or X* and Y, takentogether with the atom to which they are joined, provide a group of theformula


12. The compound as defined in claim 11 wherein R¹ is (a) alkylsubstituted with one or more groups selected from aryl, aryloxy andalkoxy, or (b) optionally substituted phenyl; B is (CR³R⁴)_(n)—R² wheren is 1 and R³ and R⁴ are each hydrogen R² is phenyl, napthyl,substituted phenyl or substituted napthyl.
 13. The compound as definedin claim 12 wherein R¹ is (aryl)alkyl, (aryloxy)alkyl, or phenylindependently substituted with one or more halogen, alkoxy, or aryloxy;R² is phenyl or napthyl independently substituted with one or morehalogen, alkyl, substituted alkyl, alkoxy; arylalkoxy, aryloxy or cyano;and Y is hydrogen.
 14. A pharmaceutical composition comprising at leastone compound of claim 1 and a pharmaceutically acceptable carriertherefor.
 15. A pharmaceutical combination comprising (a) at least onecompound of claim 1, (b) at least one other therapeutic agent selectedfrom antidiabetic agents, antihyperglycemic agents, hypolipidemicagents, antiobesity agents, antihypertensive agents, antiplateletagents, and antiinfective agents, and (c) a pharmaceutically acceptablecarrier therefor.
 16. The combination of claim 15 wherein the othertherapeutic agent is an antidiabetic agent selected from a biguanide, asulfonyl urea, a glucosidase inhibitor, a thiazolidinedione, an insulinsensitizer, a glucagon-like peptide-1 (GLP-1) or insulin.
 17. Thecombination of claim 16 wherein the antidiabetic agent is metformin,glyburide, glimepiride, glipyride, glipizide, chlorpropamide,gliclazide, acarbose, miglitol, troglitazone, rosiglitizone, and/orinsulin.
 18. The combination of claim 15 wherein the compound is presentin a weight ratio to the antidiabetic agent within the range from about0.01:1 to about 100:1.
 19. A method for treating insulin resistance,hyperglycemia, hyperinsulinemia, or elevated blood levels of free fattyacids or glycerol, obesity, hypertriglyceridemia, inflammation,atherosclerosis, diabetic retinopathy, diabetic neuropathy or diabeticnephropathy which comprises administering to a mammalian species in needthereof an effective amount of the pharmaceutical composition of claim14.
 20. A method for treating insulin resistance, hyperglycemia,hyperinsulinemia, or elevated blood levels of free fatty acids orglycerol, obesity, hypertriglyceridemia, inflammation, atherosclerosis,diabetic retinopathy, diabetic neuropathy or diabetic nephropathy whichcomprises administering to a mammalian species in need thereof aneffective amount of the pharmaceutical composition of claim 15.